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NATURAL

REGENERATIVE

THERAPIES FOR

PARKINSON'S

DISEASE David A. Steenblock M.S., D.O.

Until you know what causes Parkinson's, you cannot successfully treat it. Combining hundreds of scientific findings with my own clinical results, we now have powerful therapeutic approaches to combat Parkinson's.

Forest-For-The-Trees Publishing

San Juan Capistrano, California

2010

NO this isn't your book cover, it's just a "place-keeper"

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A CURRENT UNDERSTANDING OF PARKINSON'S

Although thousands of studies exist searching for answers as to the cause and cure

of Parkinson's, there seems to be a vast disconnect. It is as if no one has ever read

enough of the studies to come to any valuable conclusions. I found in reviewing

and comparing the scientific studies, however, that a connection does emerge

between the studies, history, and what people are actually experiencing. In

summary, it has become increasingly apparent that what is missing in the current

understanding of Parkinson's is this:

1. Damage to the mitochondria, wherein damaged mitochondria are reproducing

damaged mitochondria is not just a "part" of Parkinson's, but the basis. Not

only is damaged mitochondria the basis for Parkinson's, but also likely for

many neurological diseases, diabetes, immunological diseases, and cancers.

2. Mercury is the number one suspect today as that which is causing damage to

mitochondria, leading to so many devastating diseases. This is because of

mercury's unfettered, widespread, even brazen use in dentistry, medicine, and

industry. It's a poison we are actually injecting into people where we would

never dream of doing the same with other poisons in the same category (like

lead or arsenic). But it is also the number one suspect, because mercury has

been shown to have perhaps the highest affinity for doing damage exactly how

and where the damage is being done in Parkinson's.

3. All the "things going on" that are being observed in Parkinson's stem from the

damaged mitochondria directly or indirectly. Continuing to focus upon, study,

and address all the "things going on" without focusing upon and addressing the

mitochondria is doomed to never cure Parkinson's.

4. Many diseases are thought or known to have mitochondrial damage as the

basis. So when the day comes that man focuses upon prevention of

mitochondrial damage while also doing that which heals the mitochondria

we will likely see a revival of sorts in the medical/health fields, such as has not

been seen in medicine since the discovery of "germs", especially given the

many diseases to which damaged mitochondria is now linked.

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TABLE OF CONTENTS

MITOCHONDRIAL DAMAGE AND PARKINSON'S

Different Types of Parkinson's?

All That Is Going On In Parkinson's Emanates From The Mitochondria

Dopamine, One Of Many Neurotransmitters

Excitotoxicity: Glutamate & Nitric Oxide

Glutamate

Nitric Oxide

The Mitochondrial Connection

MERCURY

Forms of Mercury

But My Dentist Told Me Mercury Isn't Toxic

How Mercury Damages The Mitochondria

Mercury And Complex I Of The Mitochondria

Reactive Oxygen Species From Damaged Mitochondria

Mercury And The Brain's Immune System

Mercury And The Viral Connection

Some Other Toxins That Have Been Shown To Cause Parkinsonism

Rotenone

Paraquat

MPTP

The Acetogenin Family Of Compounds

Organophosphates

ALL THE "THINGS GOING ON" IN PARKINSON'S TRACE BACK TO

MITOCHONDRIAL DYSFUNCTION

Iron And Copper - Causal Or A Result?

Not Simply A Dopamine Deficiency

The Parkinson's Brain Is Toxic To Dopamine

Mitochondrial Membrane, Electron Transfer Chain Dysfunction

Calcium Homeostasis

How Does Increased Cellular Calcium Lead To Toxicity?

Genes, Genetic Mutations, Protein Mutation

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Perturbed Endoplasmic Reticulum Function

Immune System Disruption

Neurons Firing Wildly Out Of Control

Glutathione Deficiency

Up-Regulation Of Gamma-Glutamyltranspeptidase

Homocysteine

The Need For Ascorbic Acid

Are Drugs An Insult To Injury?

CAN WE REPAIR DAMAGED MITOCHONDRIA?

Mitochondrial Transplant

Stem Cell Therapy

Nutritional Supplements For Parkinson's

Hormetic Pathway - Vitagenes

Bioavailability

Acetyl-L-Carnitine

Alpha Lipoic Acid

Alpha Tocopherol

Ascorbic Acid

Astaxanthin

Black Tea Extracts

Caffeine

Carnosine

Coenzyme Q10

Creatine

Curcumin

Ganoderma Lucidum

Ginkgo Biloba

Ginsenoside

L-Theanine

NAD

Retinoids And Carotenoids

Rhodiola Rosea

Selenium

Silymarin

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Tripterygium Wilfordii

A Diet Rich In Phytochemicals

Chart of Phytochemicals

Specific Foods For Healing

Sweet Green Tea

Muscadine Grapes

Mangoes

Garlic

Soybeans

Tomatoes

Diagnostic Tests

Mercury Testing

Mitochondrial Dysfunction Tests

Urine Test Taken As First Morning After Fasting

Red Flags

MitoSciences

Clinical Mitochondrial Therapies

DMSA For Mercury Chelation

Intravenous Ginkgo

Methylcobalamin, Folate and B6

Mitochondria-Targeted Peptide Antioxidants

SS Antioxidants

RESOURCES

INDEX

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MITOCHONDRIAL DAMAGE AND PARKINSON'S

It was in 175 AD that the physician Galen described the "shaking palsy". It wasn't

until 1817 that a detailed medical essay was published on Parkinson's by London

doctor James Parkinson. We must ask ourselves, is there a single common

denominator that connects Parkinson's today to what was observed in centuries

past?

In 1991 an article in

California's Orange County

Register exclaimed: "Cause

of Parkinson's disease may

have been discovered."

Within the article they say

"Scientists may have tracked

down the long sought cause

of Parkinson's disease with

the discovery of a defect in

the 'energy factories' in

muscles of people with the

ailment." 1 The "energy factory" is your mitochondria. Much study on the

mitochondria has gone on since then. For one thing, we now know that

Parkinson's stems not from the muscles themselves, but from damage to

mitochondria in the brain which leads to a cascade of continuous, even self-

perpetuating events that damage both dopaminergic neurons and dopamine itself,

which results in the various symptoms we see in Parkinson's.

1 Paul Raeburn "Cause of Parkinson's disease may have been discovered" Simple methods may prevent

illness, researchers say. Friday, August 2, 1991 The Orange County Register.

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One of the first times mitochondrial dysfunction was described was in the 1960s,

but the wide range of disorders that would end up having mitochondrial damage as

the basis for their pathology is only now becoming apparent in 2010.2

The mitochondria is, as the Orange County article states, the "energy factory" of

your cells (see diagram of cell and its mitochondria). Of course you have cells that

make up your entire body, and you have neurons which are special messenger

types of cells which enable everything that happens in your body to occur. What

we're going to see, as we pull together the scientific studies, is that dysfunctional

mitochondria create a continuous excess of superoxide free radicals for reasons

we shall explore as we continue. Of course a healthy body would neutralize

superoxide free radicals with antioxidants.

Mitochondria have a "respiratory chain" that transfers energy across the outer

membrane. The chain is made up of Complex I, Complex II, Complex III and

Complex IV. You'll likely want to refer to the chart below as we continue to

discuss more about the mitochondria.

MITOCHONDRIAL ELECTRON TRANSPORT CHAIN Complex I Complex II Complex III Complex IV

NADH dehydrogenase

(or NADH: quinone

reductase) is an enzyme

located in the inner

mitochondrial membrane

that catalyzes the transfer

of electrons from NADH

to coenzyme Q. This is

the entry enzyme of

oxidative

phosphorylation in the

mitochondria

Succinate

dehydrogenase (or

succinate-coenzyme Q

reductase) is an enzyme

complex that exists in the

inner mitochondrial

membrane. It is the only

enzyme that participates

in both the citric acid

cycle and the electron

transport chain.

Coenzyme Q (cytochrome

c-oxidoreductase, or

cytochrome bc1 complex)

is the third complex in the

electron transport chain of

the mitochondria. It's role

is that of generating ATP

(adenosine triphosphate)

through oxidative

phosphorylation.

Cytochrome c oxidase is a

large transmembrane protein

complex found in the

mitochondrial membrane. It

receives an electron from

each of four cytochrome c

molecules, transferring them

to one oxygen molecule,

converting oxygen to two

molecules of water. In the

process it translocates four

protons across the

mitochondrial membrane to

establish a transmembrane

difference of proton

"electrochemical potential"

that ATP synthase then uses

to make ATP.

2 John Neustadt and Steve R. Pieczenik. Medication-induced mitochondrial damage and disease. From

"Molecular Nutrition & Food Research" Vol 52, Issue 7, July 14, 2008. 780-788.

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Suffice it to say here that when the function of the mitochondria's respiratory chain

complexes are impaired, there is an enhanced production of superoxide anion3

creating "mitochondrial toxins" so often referred to in literature today. These

toxins (all free radicals) include hydrogen peroxide (H2O2), peroxynitrite, and

hydroxyl radical. All of these are created by, and turn around to do further

damage to mitochondrial proteins and membrane permeability, leading to

severe mitochondrial dysfunction and destruction as well as "all the things going

on" in Parkinson's and other neurological diseases.

One mitochondrial toxin is excess nitric oxide. Some who are treating Parkinson's

are using therapies and supplements that increase nitric oxide when it is already

being generated in excess. In fact, high levels of neuronal and inducible nitric

oxide synthase were found in the substantia nigra of patients and animal models

of Parkinson's disease.4 S-Nitrosation of mitochondrial proteins appears to

contribute to the negative interactions of nitric oxide and its derivatives with the

mitochondria. When the mitochondria's supply of glutathione (an antioxidant

produced within the body) is minimal or gone, the mitochondria has little defense

against nitric oxide. Thus we have mitochondria reproducing damaged

mitochondria and production of oxygen free radicals interacting with nitric oxide

and the resultant production of peroxynitrite and a vicious cycle is perpetuated.

So what is it that can do such damage to the mitochondria?

The one damaging toxin around when Parkinson's was observed in 175 AD and

still around during James Parkinson's observations in the 1800s and still being used

today, is the toxic metal mercury. We will discuss more later exactly why

mercury is so toxic; how it does its damage; how it is the initial toxic agent;

exactly what damage it does; as well as all the subsequent damage done by the

"fallout" of mercury damage.

Of course there are other toxic substances, especially used in labs, that can cause

parkinsonian symptoms if a person is injected with or poisoned by them. For now

we're labeling mercury as our "number one" suspect. And this might be an 3 Turrens JF. Superoxide production by the mitochondrial respiratory chain. Biosci Rep. 1997;17:3-8. 4 Katia Aquilano et al. Role of Nitric Oxide Synthases in Parkinson's Disease: A Review of the Antioxidant

and Anti-inflammatory Activity of Polyphenols. Neurochem Res (2008) 33:2416-2426

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excellent time (speaking of "number one suspect") to suggest that the reason why

man has been researching, looking for the cause and cure of diseases for centuries,

yet can claim very few victories (don't believe it? Start naming all of the cures

man has discovered) is because researchers wear the researchers hat quite well, but

then neglect to put on the detective or judge hat. Meaning, they seem to do quite

well gathering up all the clues, then neglect to put them all together like a detective

would do, and then make some bold assumptions to crawl out of the box and move

forward like a judge would do. As you'll see, we'll be making bold, but intelligent

assumptions as we move forward in this book.

Let's start with the question you must be asking yourself: Why hasn't anyone

blamed mercury up until now considering all the pain and misery it appears to have

caused? For one thing, we know that mercury doesn't hang around at the scene of

the crime, but does it's deadly deed, and moves on to imbed deep within the body's

bones and tissues. Without mercury hanging around to take the blame, it is clear

why confusion exists even today, even with our modern means of testing.

This appears to be what Professor Emeritus Martin L. Pall means when he talks

about diseases sharing the same symptoms, each "initiated by a short-term stressor"

only to be followed by chronic illness that...most often lasts for life.5 Mercury is a

"short-term stressor" that has been confounding the minds of even the most

brilliant men and women for centuries. Now that we have more abundant and free

sharing of information let's hope we can put together the puzzle pieces so we can

solve the Parkinson's mystery, once and for all.

Again, we'll see very clearly later why mercury specifically damages the

mitochondria. But one indication that mitochondrial damage is part of Parkinson's

was discussed in a 1998 study: "Mitochondrial impairment as an early event in

the process of apoptosis (cell death) induced by glutathione depletion in neuronal

cells: Relevance to Parkinson's disease". They imply in the study that the

glutathione depletion is the result of the mitochondrial impairment. In reality,

glutathione transports mercury out of the body, and is also depleted by mercury, 5 Martin L. Pall. A Common Causal (Etiologic) Mechanism for Chronic Fatigue Syndrome/Myalgic

Encephalomyelitis, Multiple Chemical Sensitivity, Fibromyalgia and Post-Traumatic Stress Disorder.

martin_pall@wsu.edu.

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showing up in neurological diseases as a "glutathione deficiency" . Glutathione

depletion doesn't cause mitochondrial impairment. Mitochondrial impairment is

caused by the same thing that glutathione depletion is caused by - mercury. We

discuss later why this is so.

The aforementioned study also says, "Oxidative stress and mitochondrial

impairment, preceding DNA fragmentation, could be early events in the

apoptotic process induced by glutathione depletion." They go on to say that their

data is consistent with the hypothesis that glutathione depletion could contribute

to neuronal apoptosis in Parkinson's disease through oxidative stress and

mitochondrial dysfunction. Of course glutathione depletion leaves gaping holes in

the body's antioxidant capabilities. Without enough glutathione, the body is

rendered unable to defend against many of the deadly reactive oxygen species

(defined as any species capable of independent existence that contains one or more

unpaired electrons). This includes, for example, H2O2, peroxynitrite, and hydroxyl

radical, all of which are spewed out from damaged mitochondria. At this point if

we insert into this equation mercury's propensity for doing damage to

mitochondrial membrane and energy systems, depleting glutathione, and

fragmenting DNA, we would create a more accurate assembly of the puzzle pieces

to the Parkinson's conundrum. Why is getting to the true core of the problem of

utmost importance? Because the truth is, if you want to put out a fire, you have to

aim your extinguisher at the base.

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In the quote from the 1987 study (above) these researchers suggest that the effect

of the "poison" (mercury) on the translation mechanism associated with brain

mitochondria needs to be studied. These researchers called mercury right, a

poison. Why then is this poison still being injected into humans in 2010? I ask,

because we've known about mercury's devastating toxicity since before Christ.

More recently, people making felt hats in the 1800's, which used mercury in the

process, observed that the "hatters" went mad and had the "shakes" from mercury.6

The 1987 study talks about mercury's inhibitory effect on cytoplasmic protein.

Another study shows how mercury binds to proteins and the enzymes that

assemble proteins.7 In Parkinson's and many other neurological diseases enzyme

systems (made of proteins) that protect cells and orchestrate the proper functioning

of cells are damaged. This would include the glutamatergic system, the

dopaminergic system, and the serotonergic system.

Damaged mitochondria would have a deleterious effect in many areas of the body.

Recently, researchers studying macular degeneration and cataracts have found

extreme oxidative stress and damage to the mitochondria as the basis. So if

mercury is damaging mitochondria, what exactly is it that mercury has such an

affinity to that exists in proteins, mitochondria and glutathione? Well, here it is,

and this is big. In fact, it is the reason why mercury is our number one suspect

above all other toxins, and it is this: It is the sulfur compounds (sulfhydryl

group, thiol, mercaptan) plentiful in cells that has an extraordinary affinity to

mercury. As if that's not enough, here's a shocker: This extraordinary affinity of

mercury for sulfur has been known since before Christ. As we've mentioned, 6 Koertge HH. The Hazard of Mercury Poisoning: Don't Be a Mad Hatter. J Am Coll Health Assoc. 1965

Apr; 13:551-558. 7 A.A. Thaker and A.A. Haritos. Mercury bioaccumulation and effects on soluble peptides, proteins and

enzymes in the hepatopancreas of the shrimp Callianassa tyrrhena. Comparative Biochemistry and

Physiology Part C: Comparative Pharmacology. Vol 94, Issue 1. 1989, pp 199-205.

"The mode of neurotoxicity of methyl mercury, an environmental pollutant of

considerable concern, involves a direct inhibitory effect on cytoplasmic protein

synthesizing systems in brains cells." [Dmitrij A. Kuznetsov. Paradoxical Effect of

Methyl Mercury on Mitochondrial Protein Synthesis in Mouse Brain Tissue. Neurochemical

Research. Vol. 12, No. 8, 1987, pp. 751-753.]

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sulfhydryl groups are also called thiols and mercaptans. Interestingly, it was the

ancient Romans who coined the term "mercaptan" because of sulfur's ability to

"capture" mercury.

In macular degeneration and cataracts, researchers found that it is a sulfur

compound that makes up the protein repair system in the function and maintenance

of aging eyes.8 We're going to find as we delve into this deeper, that the

mitochondrial membrane, genes, enzymes, and antioxidants damaged by mercury,

contain a sulfur group. So you can see how it is going to be difficult at this point

to discuss damage to the mitochondria without mentioning mercury at nearly

every turn. In the next chapter we go into much more detail how mercury is highly

attracted to sulfur in the body.

You might say that mercury is much like a nuclear explosion within the body, as

mercury goes about damaging sulfhydryl groups wherever mercury shrapnel falls,

because of that high affinity between the "soft" sulfide and the "soft" metal that is

mercury. When mercury attaches to the sulfur, mitochondrial membranes are

damaged, as are protective systems that contain sulfur, like glutathione.

Man has needed to eliminate mercury as something we deliberately inject into

people on a daily basis for centuries. The complete elimination of mercury from

our environment and bodies would most likely end the one in one-hundred people

getting Parkinson's in America today (not to mention numerous other diseases).

Would a random one in, say 10,000 still get Parkinson's from extreme exposure to

another toxicant like paraquat (or even living downwind of some factory spewing

mercury into the air perhaps, or drinking water from pipes tainted by the lead used

in soldering pipes)? Of course. The world is a toxic place, and exposure to

enough of many toxins could cause neurological damage.

8 Lisa A. Brennan, Marc Kantorow. Mitochondrial function and redox control in the aging eye: Role of

MsrA and other repair systems in cataract and macular degenerations. Experimental Eye Research 88

(2009) 195-203.

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For example, some people deliberately intoxicate themselves. Extreme alcohol

consumption damages mitochondria as well.9 In one study "400 ml of ethanol"

(alcohol) was used to "remove excess thiol".10

Interestingly, in China, mercury has become one of the main causes of toxic metal

pollution in agriculture. They have found that plants with mercury toxicity show a

positive correlation with O2- (superoxide radical) and H2O2 (hydrogen peroxide) in

leaves. In addition plants poisoned by mercury show increased activity of NADH

oxidase and lipoxygenase, and damage to biomembrane lipids.11

These same

phenomena that have to do with the mitochondria, are also seen in Parkinson's and

other neurological diseases. This tells the detective in me to put these puzzle

pieces together - they're not disparate bits of information.

So where is all the mercury

coming from? The diagram to

the left shows that amalgams

("silver fillings") still rank as

the worst daily source of

mercury toxicity. Vaccines

are second, even in 2010

when everyone has been

pretty much duped into

thinking that "thimerosal"

(mercury) has been taken

completely out. Another

fallacy is that some seafood is

okay, when the truth is, all

seafood has some level of

mercury, coming from our

polluted waters.

9 Guo R., Ren J. Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and

mitochondrial damage in mice: role of mitochondrial death pathway. PLoS One 2010 Jan 18;5(1):e8757. 10 Mathias Brust et al. Synthesis of Thiol-derivatised Gold Nanoparticles in a Two-phase Liquid-Liquid

System. J.Chem.Soc.Chem.Commun 1994 11

Zhou ZS et al. Biological detection and analysis of mercury toxicity to alfalfa (Medicago sativa) plants.

Chemosphere 2008 Feb;70(8):1500-9.

http://www.doctorsaredangerous.com/articles/mercury.htm

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Consider this, if your doctor told you that the immunization you were about to

receive contained lead, would there not be an instant refusal to take the shot? How

about if the shot contained arsenic? Of course you'd refuse! This is because it is

common knowledge how toxic lead and arsenic are. In a 2010 series on CNN

about toxins in America, it was explained how the Center For Disease Control

(CDC) used to have a number they deemed a "safe" level of lead ingestion. The

story is told of one man who set about to prove, via a town that was poisoned with

lead from manufacturing, that the peoples' sickness was worsened the closer they

were to the plant. However, the sicknesses continued out in areas quite distant from

the plant as well. He proved the point, and now the CDC acknowledges there is no

safe level of lead. When will mercury be similarly acknowledged for the poison

that it is? The truth is, the body has no beneficial use for lead or mercury. It is

past time to brand mercury as the "no safe level" poison that it is so we can

eliminate it from all medicines, dental materials, foodstuff, and God-willing, our

environment once and for all.

Interestingly, the myelin sheath, known to be damaged in multiple sclerosis, is

made up in good part, of sulfhydryl groups (again, sulfhydryl groups are also

called thiols).12

There is a strong connection between people having the

thimerosal-containing (which is mostly mercury) hepatitis B injection and

subsequently presenting with multiple sclerosis.13

A hepatitis B injection from a

"multi-use" vial contains 12.5 mcg of mercury. The so-called "safe" level of

mercury has been set at .1 mcg per 2.2 pounds of body weight per day, or about .32

mcg for a newborn. A 180 pound man, therefore, should not have more than 8.2

mcg of mercury in a day according to this fictitious "safe level". Of course, if that

adult also breathes the air, has amalgam fillings, and has fish for dinner, it's easy

to see how mercury is doing the damage that it is today.

Researchers have observed that tumor necrosis factor alpha (TNFa) inhibits

mitochondrial respirations (mitochondrial respiration occurs via those complexes I-

IV previously mentioned). These same researchers note that TNFa appears to

induce mitochondrial dysfunction. They attempted to figure out where, why and

12

Thomas Weimbs and Wilhelm Stoffel. Proteolipid (PLP) of CNS Myelin: Positions of Free, Disulfide-Bonded, and

Fatty Acid Thioester-Linked Cysteine Residues and Implications for the Membrane Topology of PLP.

13 Miguel A. Hernan et al. Recombinant hepatitis B vaccine and the risk of multiple sclerosis. Neurology. 2004,

63:838-842.

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how the TNFa is generated. Nowhere in the study is mercury mentioned.14

Yet

mercury causes the release of inflammatory cytokines (defined below) like tumor

necrosis factor (TNFa). Mice exposed to mercury showed altered expression of

TNFa as well as two other cytokines, interferon and interleukin-12.15

In another study, low levels of mercury were put into drinking water for 14 days.

The results showed that low levels of mercury caused lipopolysaccharide-induced

p38 and extracellular signal-regulated kinase activation and downstream TNFa

and Interleukin-6 expression.16

Excess TNFa expression is a phenomenon seen in

ALS, MS, Parkinson's, rheumatoid arthritis and other immune, degenerative

and neurological conditions. Mercury has been shown to induce TNFa, deplete

glutathione, increase glutamate and Ca2+ toxicity, all of which are involved in

mitochondrial dysfunction, inflammation and the death of immune and neuronal

cells.17,18

TNFa is a cytokine (small protein secreted by the immune system) involved in

inflammation. It's main role is the regulation of immune cells. In Parkinson's, the

interest in TNFa is mostly in its ability to induce apoptotic neuron death.

Therefore, it is the dysregulation of TNFa that has become of interest. Putting on

my judge hat for a moment, it is obvious that focusing on TNFa is not getting to

the core of the problem. TNFa doesn't cause Parkinson's, and more importantly,

somehow "regulating" it by therapeutic means, won't cure Parkinson's. TNFa is a

result of mitochondrial damage. Some Parkinson's research focuses in on

regulating TNFa as a possible way to control Parkinson's. The truth is, stopping

damage to and repairing the mitochondria is how we can stop the "dysregulation"

of TNFa.

14

J Stadler MD et al. Tumor Necrosis Factor Alpha Inhibits Hepatocyte Mitochondrial Respiration. Ann Surg (Nov

1992) 539-546.

15 Sang Hyun Kim et al. Oral exposure to inorganic mercury alters T lymphocyte phenotypes and cytokine

expression in BALB/c mice. Archives of Toxicology. Vol 77, No 11. 2003. 613-620. 16 Sang Hyun Kim, Sharma Raghubir P. Mercury alters endotoxin-induced inflammatory cytokine

expression in liver: Differential roles of p38 and extracellular signal-regulated mitogen-activated protein

kinases. Immunopharmacology and Immunotoxicology 2005 Vol 27 123-135. 17 Noda M, Wataha JC, et al, Sublethal, 2-week exposures of dental material components alter TNFalpha secretion of THP-1 monocytes. Dent Mater. 2003 Mar;19(2):101-5 18 Dastych J, Metcalfe DD et al, Murine mast cells exposed to mercuric chloride release granule-

associated N-acetyl-beta-D-hexosaminidase and secrete IL-4 and TNFalpha. J Allergy Clin Immunol. 1999

Jun;103(6):1108-14

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While we've known about mitochondrial involvement in neurological diseases for

a while, it has only been quite recently that its true relevance has been elucidated.

In a 2009 study out of the department of chemistry, Central Washington University

we read that even iron accumulation seen in Parkinson's is a part of mitochondrial

damage:

Different Types Of Parkinson's?

The question with Parkinson's has always been, is it genetic or is it environmental?

In 2009 Author Ruben K. Dagda et al in Mitochondrial Kinases in Parkinson's

Disease: Converging Insights from Neurotoxin and Genetic Models [May, 2009]

states: "Alterations in mitochondrial biology have long been implicated in

neurotoxin, and more recently, genetic models of Parkinsonian neurodegeneration.

In particular, kinase regulation of mitochondrial dynamics and turnover are

emerging as central mechanisms at the convergence of neurotoxin, environmental

and genetic approaches to studying Parkinson's disease." They go on to say

"...evidence gathered over the last decade implicate a central role for kinase

signaling at the mitochondrion in Parkinson's and related neurodegenerative

disorders." Again, the mitochondria emerges as the "part" damaged/not working

and as these researchers state, "Interactions involving" a-synuclein (a protein

found primarily in neural tissue), LRRK2 (a protein found mostly in cytoplasm,

but also associated with the mitochondrial outer membrane), DJ-1 (also called

PARK7, a protein that seems to protect neurons from oxidative stress and cell

death) and parkin (a protein encoded by the PARK2 gene, which when mutated

has been linked to early-onset Parkinson's), are involved not causal.19

19 Ruben K. Dagda et al. Mitochondrial Kinases in Parkinson's Disease: Converging Insights from

Neurotoxin and Genetic Models. May 6, 2009.

"Our finding together with reports on iron accumulation in degenerative diseases highlight the importance of developing mitochondrial-targeted antioxidants for the therapeutic intervention of diseases associated with mitochondrial dysfunction and oxidative stress." They say that hydroxyl radical levels occur in mitochondria under oxidative stress and hydroxyl radical levels can be modulated with antioxidant enzymes and iron ligands. [Thomas C Mackey MM et al Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep 2009;14(3):102-8.]

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So what is a kinase? Kinase is also known as a phosphotransferase and is a type

of enzyme that transfers phosphate groups from high energy molecules such as

adenosine triphosphate (ATP) to a specific substrate [a molecule upon which an

enzyme acts]. This is called phosphorylation and is necessary to energize all that

needs to occur in the body - like cell division, for one thing. (An enzyme that

removes phosphate groups is known as phosphatase.) ATP is the molecule in the

mitochondria responsible for transporting energy within cells for metabolism.

ATP is produced by photophosphorylation, and by cellular respiration (via those

mitochondrial complexes I-IV we keep mentioning). All to say, damaged

mitochondria can't do their job and the entire body suffers.

Let me pause here and explain the reason for all the "science" in this book. If you

read from beginning to end you should easily understand the four main points

outlined at the very outset of the book. Whether or not you comprehend every

single term is irrelevant. You will be able to make the proper conclusions, and

from there you will be able to make wise decisions about yours or a loved-ones

Parkinson's. As doctors and medical professionals, it has always occurred to me

that we don't do patients any favors by leaving them in the dark about critical

terminology, which includes the meaning of words that apply to their condition.

All That Is Going On In Parkinson's Emanates From The Mitochondria

When we study mitochondrial function, we begin to see that nearly, or perhaps all,

of "what is going on" in Parkinson's (and many other neurological diseases) stem

from mitochondrial damage, and most likely (or most often) by mercury. This is

critical, because if we ever hope to prevent or cure Parkinson's, the focus must be

on protecting and repairing the mitochondria and this in turn would take care of

"all the things going on". A study from Cornell University states this about what

causes degeneration of the nigrostriatal dopaminergic neurons in Parkinson's

disease: "...the role of mitochondrial dysfunction gains strongest support because

mitochondria are central to a number of processes thought to be integral to PD

pathophysiology."20

(PD is the common abbreviation for Parkinson's Disease).

20 Bobby Thomas, PhD and M. Flint Beal, MD. Mitochondrial Therapies for Parkinson's Disease.

Movement Disorders Vol. 24, Suppl. 1, pp. S155-S160. 2010.

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In "biology class" perhaps you learned that mitochondria are the "batteries" of

cells. But the mitochondria is so much more. Indeed, the mitochondria reside

inside of the body's cells. Mitochondria generate adenosine triphosphate (ATP).

ATP transports chemical energy within cells for metabolism, which is why your

teacher told you mitochondria are the "batteries" of your cells. But the

mitochondria also orchestrate various biosynthesis pathways, the regulation of

calcium homeostasis and apoptotic signaling (telling cells how and when to die).

The mitochondria are also responsible for oxidative phosphorylation, lipid

metabolism, tricarboxylic acid cycle, and iron-sulfur cluster formation.

Diseases known to be caused by mutations in some of the genes associated with

the mitochondria, like Charcot-Marie-Tooth subtype 2A and autosomal dominant

optic atrophy have been known for some time. But recent studies have shown that

dysfunctional mitochondrial fission and fusion (these control the shape and

function of the mitochondria) is involved in Parkinson's disease.21

But it's not just Parkinson's that has mitochondrial damage and dysfunction and

resultant extreme oxidative stress now suspected at its core. Add to the list

schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy,

migraine headaches, strokes, neuropathic pain, ataxia, transient ischemic

attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome,

fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary

cirrhosis1. One would think that if we combine the fact that the cause of each of

these continues to baffle, the treatment continues to be hit or miss, and that nobody

is being cured - with what we now

know about mitochondrial

dysfunction, and mercury's role,

that perhaps we could finally

address the true underlying cause

of these diseases to both prevent

and find corrective therapies.

Speaking of mitochondrial

fusions, this is thought to be

involved in the transport of

mitochondria along microtubules.

Microtubules are one of the

21 Bingwei Lu, PhD. Mitochondrial Dynamics and Neurodegeneration. Current Neurology and

Neuroscience Reports 2009, 9:212-219. bingwei@stanford.edu Commonly Affected Systems in Mitochondrial Disorders http://www.mitoresearch.org/treatmentdisease.html

15 | P a g e

components of the cytoskeleton which is a cellular "scaffolding" or "skeleton"

contained within the cytoplasm of cells. A more recent observation is that fission

of mitochondria appears to be important for the correct distribution of

mitochondria along neurites and at synapses.22

Microtubules are mostly made of

beta tubulin (a protein), which (you guessed it) is readily damaged by mercury.

Dopamine, One Of Many Neurotransmitters

Parkinson's disease has been attributed to what appears to be a deficiency of

dopamine. It does appear there is not enough dopamine in the Parkinson's brain,

but "deficiency" will likely not turn out to be the best way to describe the problem.

Dopamine is one of many neurotransmitters in the body. Neurotransmitters are

how neurons connect (synapse) to do the jobs they do in the body, that is, to pass

along information from one neuron to another, like a chain reaction, ending up in

cells where the information is needed. There are approximately 100 billion

neurons in the human brain. Neurons travel throughout the body, of course. For

example, the way in which you taste food is by neurons in your taste buds relaying

the saltiness, sweetness, sourness, etc. of the food to your brain. When the

"dopaminergic" system of neurotransmitters goes awry, as in Parkinson's, bodily

functions suffer.

How does the "dopamine" neurotransmitter work? On the end of one neuron are a

collection of neurotransmitters and on the target cell there are places where the

neurotransmitters are "received" (receptor sites). There is a space in-between the

two cells called the "cleft". The neurotransmitters are released into that cleft

ultimately binding to the receptors in the membrane on the "target cell". Voila!

They've communicated. This connection was thought to be electrical when

neurons were first discovered, but in 1921 German pharmacologist, Otto Loewi,

found that neurons communicate by releasing "chemicals" which we now call

neurotransmitters.

You may have heard the names of some of these familiar neurotransmitters: amino

acid types: glutamate, aspartate, serine, GABA, glycine monoamine types:

dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline),

histamine, serotonin, melatonin others: acetylcholine, adenosine, anandamide,

nitric oxide.

22

Li, Z. et al. Cell 2004. 119, 873-887.

16 | P a g e

Receptors are those sites on cells that bind to neurotransmitters to complete the

communication between cells. People have made the analogy of the

neurotransmitter being the "key" and the receptor being the "keyhole". The

receptor is actually a protein molecule imbedded in either the outer membrane of

the cell or in the cytoplasm within the cell. A molecule that attaches to a receptor

is given a general categorical name of ligand. The ligand can be a short protein, a

neurotransmitter, a hormone, or even a toxin or a drug. Many drugs, in fact, are

created for the purpose of attaching to specific receptor sites in an attempt to alter a

disease course. Every cell has many receptors of many different kinds. Most

receptors "receive" more than one ligand. Just one example, is that the receptor

site for vitamin C also receives glucose (a consideration when we give children

sugary drinks instead of fresh fruits with vitamin C).

Neurotransmitters are classified not by how they look, but how they behave.

Therefore, if they behave differently in other functions in the body, they can

become something other than a neurotransmitter, for example, they can also

behave as hormones (defined as a chemical released by a cell in one part of the

body, that sends out messages that affect cells in other parts of the body.)

The neurotransmitter glutamate is known to modulate the neurotransmitter

dopamine's release.23,24

This is important, because food manufacturers are putting

free glutamates in processed foods by about a million tons worldwide annually.25

This issue of excess glutamate is very important because when there is

mitochondrial damage there is a resultant deficiency in the enzyme needed to

process or recycle glutamate. Thus, glutamate is known to build up and become

excitotoxic (causing neurons to synapse literally "to death") in neurological

diseases like Parkinson's.

I started off by saying that "deficiency" of dopamine may not appropriately

describe what is going on in Parkinson's. As I began to discover in my research, it

appears most likely that dopamine isn't deficient, but is being oxidized by all of the

reactive oxygen species being generated due to mitochondrial damage. We'll

23 PJ Roberts et al. Effects of L-glutamate and related amino acids upon the release of [3H] dopamine

from rat striatal slices. Brain Research 157 (1978) 391-395. 24 PJ Roberts et al. Stimulatory effect of L-glutamate and related amino acids on [3H]dopamine release

from rat striatum: an in vitro model for glutamate actions. J Neurochem 32 (1979) 1539-1545. 25 According to Leo Hepner, president of the U.K. consulting firm L. Hepner & Associates, which

specializes in fermentations and biotechnology.

17 | P a g e

discuss that more later. In addition, mitochondrial-generated reactive oxygen

species does damage to the glutamatergic system.

Excitotoxicity: Glutamate & Nitric Oxide

Glutamate is also a neurotransmitter. Researchers studying the mitochondria and

its relationship to amyotrophic lateral sclerosis (Lou Gehrig's disease) say that

in the central nervous system, glutamate is the principle stimulatory

neurotransmitter, and neuronal mitochondria play an important role in glutamate's

metabolism, as well as in the inhibitory neurotransmitter GABA (where glutamate

"excites" neurons, GABA "calms" them down). GABA, in fact, is the primary

inhibitory transmitter in the brain. Many tranquilizer drugs act by enhancing the

effects of GABA. Glycine is the primary inhibitory transmitter in the spinal cord.

Excessive stimulation of glutamate receptors is associated with neurotoxicity and

the further generation of reactive oxygen species, including excess nitric oxide.

It has been discovered that neuronal mitochondria oxidize a combination of regular

substrate pyruvate and glutamate, suggesting that mitochondria located at the

inter-neuronal junctions, especially in the spinal cord, may be particularly

vulnerable to oxidative stress.26

Glutamate

Glutamate is a neurotransmitter made from the amino acid L-Glutamine.

Glutamate causes "excitation". Where neurons synapse (connect) glutamate's role

is to stimulate the connection. In excess it is "excitotoxic", literally causing

neurons to fire wildly out of control, be damaged, even die. The healthy body

makes all the glutamate it needs for proper synapsing, and all it needs in

infinitesimal amounts.

The amino acid L-glutamine is vital in many healthful functions in the body,

including the good use of nitric oxide. In a healthy body, the following reaction is

carried out by enzymes.

Glutamate + ATP + NH3 → Glutamine + ADP + phosphate + H2O

26 Alexander Panov MD, PhD Senior Scientist, Mitochondrial Biology Group, Carolinas

Neuromuscular/ALS Research Laboratory, Department of Neurology. www.carolinasmedicalcenter.org

18 | P a g e

Note the need for ATP. The majority of ATP production takes place in the

mitochondria27

as we've previously discussed, which we now know is damaged in

Parkinson's. The result is excess glutamate buildup, and excitotoxicity, along with

excess nitric oxide. Studies clearly show that glutamate exposure to neurons

negatively affects the mitochondrial respiratory chain (Complex I), depletes

glutathione and increases nitric oxide.28

To this day, the relationship of

mitochondria to glutamate and nitric oxide seems to come under the question,

"which came first the chicken or the egg". In case you didn't hear, in 2010,

scientists decided that the chicken had to have come first because the egg can only

be formed because of a protein found in the chicken's ovaries. Thus, the egg can

only be created inside of the chicken. With regard to glutamate and nitric oxide's

relationship to the mitochondria, let us hope that researchers will soon come to the

appropriate conclusion that mitochondrial damage comes first. This is important,

because it is the mitochondria that needs our immediate attention, and not so much

glutamate or nitric oxide.

Note in the above study the words "under physiological conditions". This means

under normal, healthy bodily conditions. They do say that under pathological

conditions there is elevated glutamine and ammonia (these occur as byproducts

when glutamate is recycled). They make note of this occurring in conditions of

liver failure. Mercury damage also leads to the endogenous production of excess

excitotoxic glutamate and nitric oxide. In fact, research has shown that

glutamine synthetase, the enzyme that is necessary to convert glutamate back to

glutamine (for recycling) in astrocytes (are a type of glial cells in the brain,

27 Lodish H. et al. Molecular Cell Biology 5th Ed. (2004) New York WH Freeman ISBN 9780716743668. 28 Angeles Almeida et al. Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial

dysfunction and glutathione depletion. Brain Research. Vol 790, Issues 1-2 (April 1998) 209-216.

Under physiological conditions, astrocytes take up L-glutamate from the synaptic gap,

metabolize it to L-glutamine and return it to neurons, where L-glutamine is metabolized

to L-glutamate and stored in neurotransmitter vesicles. However, under pathological

conditions, such as hepatic failure, L-glutamine and ammonium are elevated globally in

the brain. [Svoboda N, Kerschbaum HH. L-Glutamine-induced apoptosis in microglia is

mediated by mitochondrial dysfunction. Eur J Neurosci 2009 Jul;30(2):196-206.]

19 | P a g e

discussed in more detail later), is inhibited by mercury (HgCl2) in vitro.29

In either

case, what is being observed is a glutamatergic system not working properly.

In addition, a deficiency of glutamine synthetase leads to an impairment of

excitatory amino acid transporters (EAAT) which are found in neuronal and glial

membranes.30

This results in the build-up of excess excitotoxic glutamate in

astrocytes (a type of glial cell) as well as in the extracellular matrix, while

simultaneously there is a decrease of glutamate inside neurons.31

Excess glutamate

in the extracellular space over stimulates the NMDA receptor (a glutamate

receptor).27,32,33,34

The over stimulation of the NMDA receptor results in alterations

to calcium homeostasis.35

Influxes of calcium results in a change in membrane

potential and the initiation of apoptosis, and ultimately, cell death.36

For everyone, consuming free glutamates every single day is unhealthy to say the

least. Glutamates added to foods is toxic by extreme excess, and something that

must be dealt with. But for people with damaged mitochondria and resultant

deficiencies in glutamate synthetase, consuming free glutamates adds tremendous

insult to injury.

When did we start adding free glutamates (which, in its pure form, is known as

monosodium glutamate, or MSG) to our foods? Monosodium glutamate was

discovered in 1908 by Kikunae Ikeda, a Japanese chemistry professor. For

29 JW Allen et al. Mercuric chloride, but not methylmercury, inhibits glutamine synthetase activity in primary cultures of cortical astrocytes. Brain Res., 891, (2001)148-157. 30

Y Shigeri et al. Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev

45 (July 2004) 3:250-265.

31 VA Fitsanaki & M Aschner. The importance of glutamate, glycine, and gammaaminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity. Toxicol Appl Pharmacol, 204, (2005)343-354. 32 JW Allen et al. The consequences of methylmercury exposure on interactive functions between astrocytes and neurons. Neurotoxicology, 23, (2002)755-759. 33 E Mariussen & F Fonnum. The effect of polychlorinated biphenyls on the high affinity uptake of the neurotransmitters, dopamine, serotonin, glutamate and GABA into rat brain synaptosomes. Toxicology, 159, (2001)11-21. 34 E Matyja & J Albrecht. Ultrastructural evidence that mercuric chloride lowers the threshold for glutamate neurotoxicity in an organotypic culture of rat cerebellum. Neurosci Lett 158, (1993) 155-158. 35 DW Choi. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58, (1985) 293-297. 36 TL Limke et al. Disruption of intraneuronal divalent cation regulation by ethylmercury: are specific targets involved in altered neuronal development and cytotoxicity in methylmercury poisoning? Neurotoxicology, 25, (2004)741-760.

20 | P a g e

centuries Japanese cooks had been using various fermented food substances that

when added to their cooking made food taste better. As Professor Ikeda

discovered, the substance turned out to be L-glutamate. Monosodium glutamate

was first marketed in 1909 as "Accent". Since then, the evils of free glutamates

have been uncovered as people suffered from what was at first described as the

"Chinese Food Syndrome". Now food manufacturers have become a bit sinister in

their attempts to hide "MSG" by using various substances that contain free

glutamate (see below). Today entire websites are maintained by people who suffer

from the symptoms of excess free glutamates which include everything from

severe migraines to neurological symptoms. It is said that over a million tons of

free glutamate sources are sold and put into foods worldwide. Defenders of free

glutamates just haven't done their homework.

MSG is just one source of free glutamates that most people have heard of. Most

people think MSG is a preservative. But it's not, it's an "excitotoxin", exciting the

tastebuds, fooling them into thinking inferior food is far superior in taste than it

actually is. The problem is that glutamates don't just stimulate taste buds, but also

causes excessive excitation of neurons in the brain and anywhere neurons are

synapsing. Where there is damaged mitochondria, excess glutamate activity is

already occurring because glutamate-clearing enzyme systems are damaged or

missing. So ingesting glutamates in food becomes yet another neurological

poison adding fuel to the fire.

The worst part to the glutamate story is that food manufacturers hide free

glutamates in up to 40 different additives so the consumer won't know they're

ingesting it. Some names of compounds with hidden free glutamates are: yeast

extract, hydrolyzed (anything), calcium caseinate, sodium caseinate, yeast food

or yeast nutrients, autolyzed (anything), gelatin, textured protein, vetsin,

ajinomoto, carrageenan, bouillons and broths, stock, whey protein, whey

protein concentrate, whey protein isolate, any "flavors" or "flavoring",

maltodextrin, citric acid (E330), protease added, anything "enzyme modified",

malt extract, soy sauce, soy protein (unless it specifically says "whole soy") and

anything fermented. Often when something is "protein fortified", beware. That

protein is actually fermented, isolated, autolyzed, or textured, and thus full of free

glutamates that are generated in the process.37

37 http://www.truthinlabeling.org/Ingredients_WithEnumbers_6.4.10.pdf

21 | P a g e

Glutamate, like mercury is ubiquitous. Wherever you see a food with a long list of

ingredients, many you can't even pronounce, one or more of those ingredients is

likely a free glutamate source. The daily ingestion of free glutamates is far in

excess of what the body can handle. It isn't surprising that we find glutamates

being implicated in dozens of diseases, especially where damaged neurons are

involved, as in Parkinson's.38

Glutamates don't cause the initial disease, but are

being produced within the body excessively because of the disease in progress.

Here's an interesting thought. When you note that the Asian population seems far

less affected by their extremely high level of free glutamate consumption, also note

that they regularly drink sweet green tea, highest of all green teas in L-Theanine, a

glutamate antagonist. There is some chatter about there being a synergistic

benefit when L-Theanine is consumed in combination with caffeine (both of which

are found in sweet green tea).

Researchers have more recently found neurological disorders to be associated with

a deficiency in glutamate dehydrogenase.39

Glutamate dehydrogenase is found in

the mitochondria and is an enzyme that both breaks down and builds up L-

glutamate. Like "all the other things going on" in Parkinson's, the lack of

glutamate dehydrogenase has been looked at as a possible cause of neurological

diseases. However, when you put this finding into proper perspective, knowing

that mitochondrial damage is the basis for Parkinson's, you can see that a glutamate

dehydrogenase deficiency is due to damaged mitochondria. Glutamate

dehydrogenase deamination (breakdown) of glutamate requires NAD+

(nicotinamide adenine dinucleotide). NAD+ is also involved in the mitochondrial

family of transport proteins, precisely where the mitochondria has been damaged.

In Humans, the activity of glutamate dehydrogenase is controlled through ADP-

ribosylation, a covalent modification carried out by the gene sirt4. This regulation

is relaxed in response to caloric restriction and low blood glucose. It could very

well be that the Ketogenic diet (high fat and protein, low carbohydrate) shown

helpful against epileptic seizures and sometimes helpful for Parkinson's has

everything to do with the fact that blood glucose is kept low, increasing glutamate

dehydrogenase, and consequently lowering excessive glutamate activity which

fires neurons excessively (hence, a seizure or tremors). In fact, various

38 Bittigau P, Ikonomidou C. Glutamate in neurologic diseases. J Child Neurol. 1997 Nov;12(8):471-85. 39 Andreas Plaitakis MD et al. Neurological disorders associated with deficiency of glutamate

dehydrogenase. Annals of Neurology. Vol 15, Issue 2. 144-153. October 7 2004.

22 | P a g e

modifications of the ketogenic diet, in attempts to make the diet less restrictive, but

still creating a stable/low blood glucose have been shown to be as effective as the

Ketogenic diet.40

Another damaging effect of glutamate excitotoxicity is that it has been shown to

lead to the excess production of nitric oxide. Glutamate excitotoxicity causes the

rise of intracellular calcium which then increases neuronal nitric oxide synthase

activity, the nitric oxide combines with superoxide anion to form peroxynitrite,

and it is the peroxynitrite that has been shown as the main damaging molecule in

dopaminergic neuronal cells. Thus, it is the production of large amounts of nitric

oxide that are thought by many to contribute to dopaminergic neuron death.41

In

case this is getting confusing, just remember. It all started with mercury damaging

the sulfhydryl groups on the mitochondrial membrane (the various complexes that

transport energy across the membrane). This in turn leads to a cascade of events

that reduces antioxidants like glutathione, and increases excitotoxic glutamates and

damaging nitric oxide.

Nitric Oxide

Nitric oxide is a molecule in the body made up of one atom of nitrogen and one

atom of oxygen. It is a "free radical" because it has an unpaired electron looking

for a mate. Nitric oxide is actually an important "messenger molecule" because it

is highly reactive, and can thus react in some positive functions throughout the

40 Kossoff EH, et al.. A modified Atkins diet is effective for the treatment of intractable pediatric

epilepsy. Epilepsia. 2006;47:421–424 41 Marchetti et al. Glucocorticoid receptor-nitric oxide crosstalk and vulnerability to experimental

parkinsonism: pivotal role for glia-neuron interactions. Brain Research Reviews. 48 (2005) 302-321.

When the production of nitric oxide is abundant and uncontrolled, it results in

damaging effects mainly mediated by its reactive species. In Parkinson's disease, nitric

oxide increase is caused either by over expression of nitric oxide synthases or by other

mechanisms, including glutamate excitotoxicity. The latter event causes the raise of

intracellular calcium levels, which in turn increases nNOS dephosphorylation and its

enzymatic activity. Nitric oxide reacts with superoxide anion formed during dopamine

metabolism thus generating peroxynitrite that is considered one of the main damaging

molecules in dopaminergic neuronal cells. [Katia Aquilano et al. Role of Nitric Oxide

Synthases in Parkinson's Disease: A Review on the Antioxidant and Anti-inflammatory

Activity of Polyphenols. Neurochem Res (2008) 33:2416-2426.]

23 | P a g e

body. As with so many compounds in the body, proper levels are good, but too

much or too little is bad. As a messenger molecule nitric oxide is involved in

many physiologic processes, including vasodilatation, immune response and

neurotransmission.42

Proper levels of nitric oxide are necessary to keep blood

pressure normal. Nitric oxide is only the beginning. It's what happens when nitric

oxide reacts with a dysfunctional mitochondrial electron transfer chain, and

reactive oxygen species being spewed from the mitochondria that is of critical

importance to the health of dopaminergic neurons.

Nitric oxide is produced from the amino acid arginine via the enzymes inducible

nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and

neuronal nitric oxide synthase (nNOS). Only recently has an additional form of

nitric oxide synthase been discovered in the mitochondria (mtNOS). This enzyme

is currently being researched, but is thought to actually be iNOS, eNOS or nNOS

translocated into mitochondria to participate in the regulation of the electron

transfer chain.43,44

The electron transfer chain (ETC) is the part of the

mitochondria we've previously mentioned as Complex I-IV (refer back to our chart

at the beginning of the book)

The study above says superoxide production occurs during dopamine metabolism

as if somehow dopamine produces the damaging molecule. This may be an

observation that is not fully descriptive of what really happens. Because we now

know that when the mitochondrial membrane is damaged, there is long-term

exposure of mitochondrial respiratory activities to nitric oxide which increases the

excess production of superoxide anions (O2-), hydrogen peroxide and

peroxynitrite. The excess production of these aforementioned reactive oxygen

species results in a persistent inhibition of NADH:cytochrome c reductase

activity (Complex III) which has been shown to inhibit Complex I.45

We also

42 WK Alderton et al. Nitric oxide synthases: structure, function and inhibition. Biochem (2001) 357:593-

615. 43 MC Carreras et al. Nitric oxide, complex I, and the modulation of mitochondrial reactive species in

biology and disease. Mol Aspects Med (2004) 25:125-139. 44 C Giulivi et al. Nitric oxide regulation of mitochondrial oxygen consumption I: cellular physiology. Am J

Physiol Cell Physiol (2006) 291:C1225-C1231. 45 Riobo NA et al. Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through

peroxynitrite formation. Biochem J. 2001 Oct 1;359(Pt1):139-45.

24 | P a g e

know that glial cells produce excessive levels of nitric oxide in Parkinson's disease

which would also be neurotoxic for dopaminergic neurons.46

Thus, one pathway leading to excess nitric oxide involves damage to mitochondrial

Complex I activity of the electron transport chain (likely by mercury). There

are other toxins that are actually used in labs to induce "parkinsonian" symptoms

(discussed more later). Let's just say here that you will see that these other toxins

are now known to induce parkinsonianism by damaging the mitochondria.

When complex I is damaged, impairing oxidative phosphorylation, we see an

enhancement of excitotoxicity (excess glutamate and thus excess neuronal

synapsing). Excitotoxicity leads to an influx of calcium, followed by activation of

neuronal nitric oxide synthase. The excess nitric oxide combines with superoxide

to form peroxynitrite and neurotoxicity ensues. During all of this, thiols (in the

mitochondrial membrane as well as the antioxidants attempting to come to the

rescue) react rapidly with a metabolite of nitric oxide to form S-nitrosothiols47

(another "reactive nitrogen species", also known as thionitrites because they are a

nitroso group attached to the sulfur atom of a thiol).

We know that DNA damage occurs by direct reaction with reactive nitrogen

species wherein repair processes are inhibited by lipid peroxidation products

and/or hydrogen peroxide. The fragmenting of mitochondrial DNA can be

attributed to reactive nitrogen species.48,49

Protein modifications seen in Parkinson's are caused by nitric oxide through

nitrosylation and nitration. For example, during nitration, a nitro (-NO2) group is

46 S. Hunot et al. Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience

Vol 72, Issue 2. May 1996. 355-363. 47 Christina C. Dahm et al. Persistent S-Nitrosation of Complex I and Other Mitochondrial Membrane

Proteins by S-Nitrosothiols but Not Nitric Oxide or Peroxynitrite: Implications for the interaction of nitric

oxide with mitochondria. Journal of Biological Chemistry. Vol 281. No 15. April 14, 2006. 48 PK Kim et al. The regulatory role of nitric oxide in apoptosis. Int Immunopharmacol (2001) 1:1421-

1441. 49 Sten Orrenius et al. Mitochondria, oxidative stress and cell death. From "Oxidants And Antioxidants in

Biology" Book of Abstracts. Translational Redox Science Co-Sponsored by the Linus Pauling Institute.

Oxygen Club of California 2010. P. 26

25 | P a g e

added onto tyrosine to form nitrotyrosine. Increased nitrotyrosine was detected in

the substantia nigra of in vivo models of Parkinson's.50

In fact, increased nitrotyrosine was found in the core of Lewy bodies (abnormal

aggregates of protein that develop inside nerve cells ) where a specific nitrated

form of a-synuclein was also found. Of course, a-synuclein is also found to be

highly expressed in the substantia nigra of Parkinson's patients.51,52

S-nitrosylation occurs when nitric oxide reacts with proteins through their reactive

cysteine thiols.53

Modified proteins seen in neurological diseases like Parkinson's

include N-methyl-D-Aspartate receptor (NMDAR), p21ras

, caspase 3 and 9,

Nuclear Factor ӄB (NF-ӄB) and others.54

In addition, increased levels of nitric oxide leads to specific S-nitrosylation of

protein-disulphide isomerase (PDI). The up-regulation of PDI seems to be an

adaptive response to protect neuronal cells, but S-nitrosylation of PDI leads to the

accumulation of polyubiquitinated proteins leading to neuronal cell death via

endoplasmic reticulum stress.55

Nitric oxide has an affinity for heme (iron-containing molecule). Thus,

nitrosylation or oxidation of protein thiols and removal of iron from iron-sulphur

clusters in the mitochondria by nitric oxide will inhibit ATP synthesis.56

Some

suggest that nitric oxide could actually be the primary compound involved in

inhibiting complex I in dopaminergic neurons.57,58

50 S Pennathur et al. Mass spectrometric quantification of 3-nitrotyrosine, orthotyrosine, and o,o'-

ditryrosine in brain tissue of 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine-treated mice, a model of

oxidative stress in Parkinson's disease. J Biol Chem 274:34621-34628. 51 PF Good et al. Protein nitration in Parkinson's disease. J Neuropathol Exp Neurol. (1998) 57:338-342. 52 BL Giasson et al. A hydrophobic stretch of 12 amino acid residues in the middle of a-synuclein is

essential for filament assembly. J Biol Chem. (2001) 276:2380-2386. 53 DT Hess et al. S-nitrosylation: spectrum and specificity. Nat Cell Biol (2001) 3:E46-E49. 54 DT Hess et al. Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol (2005) 6:150-

166. 55 T Uehara et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to

neurodegeneration. Nature (2006) 441:513-517. 56 S Moncada. Nitric oxide and cell respiration: physiology and pathology. Verh K Acad Geneeskd Belg

(2000) 62:171-179 discussion 179-181. 57 AH Schapira. Etiology of Parkinson's disease. Cell Death Differ (2007) 14:1261-1266.

26 | P a g e

All of this, of course, occurs because mitochondria have been damaged by an

initial stressor, most likely, most often mercury. It is important to keep the initial

stressor in mind because just fighting nitric oxide won't cure the underlying

problem.

In fact, because nitric oxide is being produced in excess and creating highly toxic

metabolites, this would indicate a need to inhibit excess nitric oxide, not attempt to

stimulate it.59

Yet some studies recommend therapies or supplements to increase

nitric oxide. Creatine and arginine would be examples of two supplements in

part aimed at increasing nitric oxide. Again, nitric oxide overproduction is what

research has shown to be the event significantly contributing to death of

dopaminergic neurons, via oxidative damage on cellular lipids, proteins and

DNA.60,61

A bit on the flip side, some researchers, in an attempt to protect good nitric oxide

in the vasculature (eNOS), and in the immune and cardiovascular system (iNOS)

have developed a class of "nonpeptide nNOS-selective inhibitors". The thinking

is that if they can keep nitric oxide down in the brain, but up everywhere else,

they'd solve the problem. Of course, they are looking for a drug to do this. They

still call it a "potential" therapy.62

But right off the bat, there's a problem. It is

inducible nitric oxide (iNOS) synthase that has been found in motor neuron

mitochondria and Schwann cells, and thought to contribute to disease mechanisms

in ALS.63

This once again reinforces the need to aim our "extinguisher" at the base

of the fire, and not at "all the things going on".

58 MC Carreras et al. Nitric oxide, complex I, and the modulation of mitochondrial reactive species in

biology and disease. Mol Aspects Med (2004) 25:125-139. 59 MF Beal. Excitotoxicity and nitric oxide in Parkinson's disease pathogenesis. Ann Neurol.

1998;44:S110-114. 60 JB Schulz et al. Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-

induced neurotoxicity in mice. J Neurochem (1995) 64:936-939. 61 P Hantraye et al. Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in

baboons. Nat Med (1996) 2:1017-1021. 62 Richard B. Silverman. Design of Selective Neuronal Nitric Oxide Synthase Inhibitors for the Prevention

and Treatment of Neurodegenerative Diseases. Accounts of Chemical Research. Vol 42. No 3. March

2009. 439-451. 63 Kevin Chen et al. Inducible nitric oxide synthase is present in motor neuron mitochondria and

Schwann cells and contributes to disease mechanisms in ALS mice. Brain Struct Funct (2010) 214:219-

234.

27 | P a g e

In 2010 researchers Khan and Ghosh report on the herb Withania somnifera for

possibly lowering nNOS.64

The benefit of looking to herbal therapies is that herbs

tend to go where they are needed, and do their job without the dangerous side-

effects of man-made drugs.65

Another "herb" a type of edible mushroom contains polysaccharides that were

found to prevent inflammation through the inhibition of both Cox-2 and nitric

oxide production, dose dependently.66

Compounds that inhibit nitric oxide biosynthesis were shown to significantly

protect dopamine neurons against manganese chloride (a compound known to

stimulate microglia to produce reactive oxygen species).67

Indeed, the "good guy" "bad guy" nature of nitric oxide is a good example of why

trying to control events far from the source of the problem can be highly

frustrating, useless, and even detrimental. It would appear that neither stimulating

nitric oxide nor making heroic efforts to squelch it, is the answer in Parkinson's and

other neurological diseases. Trying to regulate all the "things going on" can (and

has) failed thus far. What would be safe and beneficial, however, is consuming

copious plant polyphenols as antioxidants against the damaging effects of nitric

oxide.

First and foremost, however, the most important step that can be taken to stop the

excess production of nitric oxide is to eliminate the consumption of all dietary free

glutamates. It goes without saying, of course, that we should aim our efforts at

truly repairing the mitochondria, while keeping mercury and any other poison from

damaging it further. In this way all the toxic things going on as a result, like

excess nitric oxide production, should cease.

The Mitochondrial Connection

64 Zaved Ahmed Khan and Asit Ranjan Ghosh. Possible nitric oxide modulation in protective effects of

Withaferin A against stress induced neurobehavioural changes. Journal of Medicinal Plants Research Vol

4(6) 490-495. 18 March, 2010. 65 Alan Tillotson. Constituents and Tissue Affinities in Herbal Medicine. Journey of Dietary Supplements.

Vol 5. Issue 3. November 2008. 238-247. 66 Byung Ryong Lee et al. Agrocybe chaxingu polysaccharide prevent inflammation through the inhibition

of COX-2 and NO production. BMB Reports. June, 2009. www.bmbreports.org 67 Ping Zhang et al. Microglia enhance manganese chloride-induced dopaminergic neurodegeneration:

Role of free radical generation. Experimental Neurology 217 (2009) 219-230.

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Within the now hundreds of studies making the mitochondrial connection to

neurological and immunological diseases, none thus far have clearly elucidate how

the mitochondria got damaged in the first place. They all state the obvious, that

oxidative damage both to and from the damaged mitochondria are "involved." I'm

sure you can see how we need to take this a step further!

As we move forward, never lose sight of the fact that mitochondria are self-

replicating units within the cells. Damaged mitochondria that don't die altogether,

will produce more damaged mitochondria. In 1999 Kowald observed the "slow

accumulation of impaired mitochondria".68

In 2009, Baqri et al observed that

damage to mitochondria involves the disruption of mitochondrial DNA, but that

this does not hinder mitochondria from replicating, i.e., damaged mitochondria

produce damaged mitochondria.69

Some say it is very difficult to study the mitochondria because when you isolate

them for study in a lab, or view them in a sacrificed animal, they aren't in their live

active state. Or as one group of researchers put it: "as with all mitochondrial

incubations, the environment and substrate availability depart considerably from

the physiological."70

Nevertheless, much has been learned. But again, what seems

to elude researchers to this day is what would cause that initial defect in or damage

to the mitochondria. We need to explore this question thoroughly, because until

we are confident we have unearthed the initial stressor, we will continue to study

"all the things going on" without understanding why.

So what damages the mitochondria? Mercury must be our number one suspect

today, given this distinction by virtue of its prevalence and deliberate injection and

placement into bodies. Mercury is well known to damage the mitochondria.71

68 Axel Kowald. The mitochondrial theory of aging: Do damaged mitochondria accumulate by delayed

degradation? Experimental Gerontology. Vol 34, Issue 5. August 1999. 605-612. 69 Rehan M. Baqri et al. Disruption of Mitochondrial DNA Replication in Drosophila Increases

Mitochondrial Fast Axonal Transport In Vivo. November 17, 2009. www.plosone.org 70 Sung W. Choi et al. Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram

scale: Spare respiratory capacity and stochastic mitochondrial failure. J Neurochem 2009 May; 109

(4):1179-1191. 71 Pilar Carranza-Rosales et al. DMPS reverts morphologic and mitochondrial damage in OK cells exposed

to toxic concentrations of HgCl2. Cell Biology and Toxicology. Vol. 23, Number 3/May, 2007 p 163-176.

29 | P a g e

This fact is highly critical in Parkinson's, because as you will soon see, just giving

dopamine is not the answer. We can now clearly see that damaged mitochondria

generate the toxic environment in the brain that is killing dopaminergic neurons,

and oxidizing dopamine itself. In case you're not yet convinced that mercury is our

number one suspect, don't feel badly. Man has been fooled for thousands of years.

However, once you learn exactly how and why mercury earns this villainous

distinction, you will likely change your mind.

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MERCURY

Within this chapter we will make optimal use of our detective and judging skills, to

prove beyond a shadow of a doubt, that mercury is the number one suspect,

causing devastating damage to mitochondria as well as protective systems within

the body.

Mercury was known to be neurotoxic in the time of Julius Caesar and the Roman

Empire, 100-44 BC. It was well-known that people who worked in the mercury

mines at that time (they mined mercury from cinnabar, an ore containing mercuric

sulfide) went crazy, suffered neurological symptoms, even died within a few years.

Indeed, we've proven from vials of mercury found in ancient caves, that the deadly

substance has been harnessed and used since antiquity.72

What you will likely find

amazing, as do I, is that over the centuries, man has never lost sight of the

knowledge that mercury is highly toxic. Why is that amazing? Because we use it

liberally in medicine, dentistry and industry, knowing it's one of the most toxic

things on earth.

In fact, mercury is

currently third on

the list of the

Center for Disease

Control's most

toxic substances in

our environment.73

So why do we put

even "trace"

amounts of

mercury into anything? Especially into things that we inject or implant into our

bodies (like immunizations and amalgam fillings). Yet, in 2010, mercury is still

used in the medical field, as well as in "energy saving" lightbulbs, and in industry

which spews it into our waterways, polluting seafood. 72 Mercury - element of the ancients. Center For Environmental Health Sciences. Dartmouth College. 73

http://www.atsdr.cdc.gov/cercla/07list.html

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The 2007 CERCLA table goes on to list a total of 275 toxic substances. You

would certainly recognize many of them, like cadmium, DDT and chloroform. If

you go to their website and take a look at the entire list you'll find that aluminum,

fluoride and other familiar substances are on it as well. But mercury is #3 only

after lead and arsenic (would you ever expect a doctor to inject you with either of

those?) I ask again, why can he inject patients with mercury with impunity?

CERCLA (The Comprehensive Environmental Response, Compensation and

Liability Act) is a government agency that establishes requirements for other

agencies within the government, like the Environmental Protection Agency. The

way substances are ranked, is based upon frequency of occurrence at sites studies,

toxicity of the substance, and potential for human exposure. Considering all the

confusion about what is causing our epidemic of neurological and other diseases,

today, it would behoove us all to take a serious look at this list. Fluorine, for

example, is way down near the bottom of the list at #211. As "detectives"

shouldn't we conclude from mercury's #3 ranking versus fluorine's #211 ranking

that you are perhaps 208 times more likely on a daily basis to be poisoned by

mercury than fluorine?

Yet even healthcare professionals are confused, throwing up their hands and

saying, there are hundreds of poisons that can cause neurological diseases. Or

worse, are so confused, it becomes easier to believe that only "spontaneous internal

combustion" causes neurological diseases. The truth is, experiments with 18 other

heavy metals have not produced even one of the many biochemical and

histological diagnostic signs seen in the neurological disease Alzheimer's which

shares many of the same biomarkers as Parkinson's.74

So why mercury and not lead or arsenic as our number one suspect? We've already

mentioned that immunizations are laced with mercury, not lead or arsenic. But

also, as has previously been mentioned , it all has to do with mercury's

extraordinary affinity to sulfur, as in sulfhydryl groups found abundantly in the

brain and nerves. In fact, mercury has possibly the highest affinity to sulfur of any

substance known. I spoke of a "shocker" before, as to how it was known before

74 FDA Panel Submission Mercury and Neurotoxicology.

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Christ of mercury's affinity for sulfur. In fact, mercury was written about in

ancient writings on many occasions. Probably the first ever recorded chemical

reaction was by Theophrastus (371 BC - 286 BC) wherein he wrote of a "magical"

reaction that occurs when the ore cinnabar is rubbed with vinegar in a copper

mortar.75

Pure mercury is produced.

HgS (cinnabar) + Cu (mortar) Hg (mercury) + CuS (copper sulfide)

In his "Book 33" chapters 36 to 41 Pliny the Elder (23 AD - 79 AD) wrote

extensively about the cinnabar industry wherein he speaks of mercury's

extraordinary affinity for sulfur, and of mercury's toxicity. Of course they didn't

know about the mitochondria back then, but today we know that the mitochondrial

membrane is made up of protein-bound sulfhydryl (SH) groups. Sulfur's presence

in the body doesn't stop there. Sulfhydryl groups are also present in the cytoplasm

of all cells of the body. Many proteins are "sulfur proteins".

Sulfhydryl groups are a sulfur and hydrogen bond, and form complexes with many

metal ions, but most especially those considered to be "soft metals". Soft metals

include mercury, platinum, palladium, silver, and gold. Methylmercury is a "very

soft" metal and actually appears to have the strongest affinity of all metals for

sulfhydryl groups. When the sulfhydryl group is part of a protein, as would be

found in a cell membrane, because of the affinity between the soft sulfide and the

soft metal, the protein is deformed and inactivated as seen in heavy metal

poisoning, and ultimately, in neurological diseases.

It is interesting to note that silver and gold are both on the list of soft metals. So

why aren't they both toxic like mercury? People actually take "colloidal silver" as

a safe, natural antibiotic supplement. It all has to do with how each metal's

individual atoms react with other atoms. It just so happens that mercury has a

unique electronic configuration where electrons fill up all the available spots in its

electron orbits (every electron is paired). This configuration strongly resists

removal of an electron. Mercury's electron configuration allows it to form weak

bonds by taking on extra electrons ("charging it"), and readily giving them up

75

Dr. Gerald Kutney. "Sulfur - History, Technology, Applications & Industry" (2007) ChemTec Publishing. Pg 3.

33 | P a g e

again.76

Many other metals can form strong bonds, like gold, which renders the

metal much less harmful or even harmless. But mercury is not rendered harmless,

the core atom is unchanged as it takes on and gives up electrons, while going about

doing continuous devastating damage. You might say that mercury is like an

internal nuclear explosion.

Any amount of mercury is toxic, meaning when someone tells you your flu shot has

"just a trace", the truth is you are being injected with a poison that will eventually

alter your life miserably. Each time you ingest mercury via amalgams, eating fish,

getting an immunization that contains thimerosal or breathing in vapors from a

broken fluorescent or "energy saving" lightbulb, that mercury goes to work doing

devastating damage to the cells in your body. In fact, in 1973, William

Ruckelshaus, head of the newly formed (1970) Environmental Protection Agency,

declared, "There is no safe level of exposure to mercury." To this, I have to ask,

"Was anybody listening?" As of 2010, mercury is still in wide use in dentistry,

medicine and industry.

Forms Of Mercury

Outside of the body, mercury is found as elemental (Hg2+

), inorganic (ethyl

mercury or iHg) and organic (methyl mercury MeHg). Whatever form, the

76 Norrby, L.J. (1991). "Why is mercury liquid? Or, why do relativistic effects not get into chemistry

textbooks?".Journal of Chemical Education 68: 110

SILVER'S ORBITS

Note many electrons unpaired

MERCURY'S ORBITS Note all electrons are paired

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toxicity of mercury once inside the body lies in how it binds to sulfhydryl groups

on proteins in the body.77

Of course proteins make up virtually everything in the

body - your genes, cells, and tissues - so altering them alters their

function.78,79,80,81,82

Nevertheless, methyl mercury has been dubbed the most toxic because it is a

vapor, easily absorbed through skin and gut, and it easily crosses the blood-brain

barrier. This is the mercury that vaporizes off of dental amalgams every time you

chew on something. On the other hand, liquid elemental mercury, or inorganic

mercury is poorly absorbed, but once inside the brain is even more neurotoxic than

methyl mercury through astrocyte dysfunction .83

Tragically a chemistry professor at Dartmouth, Karen Wetterhahn, died in 1997

from just a couple of drops of dimethyl mercury on the latex-gloves she was

wearing. She was poisoned in August of 1996, and died in June of 1997. The

chain reaction events that occurred with the mercury poisoning only showed up as

deadly by the time she was hospitalized nearly a year after the tragic event.84

Even today there is much confusion as to whether there is a "safe" mercury versus

a "toxic" mercury. It was once thought that the blood-brain barrier (a system of

tight junctions around capillaries and exists only in the central nervous system to

protect the brain from dangerous foreign molecules) prevents mercury from

entering the brain and thus doing any damage there. (A foolish assumption

77 http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=115&tid=24 78 AI Cabanero et al. Effect of animal feed enriched with Se and clays on Hg bioaccumulation in chickens: in vivo experimental study. J Agric Food Chem (2005) 53, 2125-2132. 79 LG Costa et al. Developmental neuropathology of environmental agents. Annu Rev Pharmacol Toxicol (2004) 44, 87-110. 80 VA Fitsanakis et al. The importance of glutamate, glycine, and gamma-aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity. Toxicol Appl Pharmacol (2005) 204, 343-354. 81 J Gailer et al. Structural basis of the antagonism between inorganic mercury and selenium in mammals. Chemical Research in Toxicology, (2000)13, 1135-1142. 82 A Szasz et al. Effects of continuous low-dose exposure to organic and inorganic mercury during development on epileptogenicity in rats. Neurotoxicology (2002) 23, 197-206. 83 A Yasutakeet al. Induction by mercury compounds of brain metallothionein in rats: HgO exposure induces long-lived brain metallothionein. Arch Toxicol, 72, (1998)187-191. 84 Dartmouth Toxic Metals Research Program: A Tribute to Karen Wetterhahn.

http://www.dartmouth.edu/~toxicmetal/HMKW.shtml

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considering the toxic history of mercury, but we'll proceed.) What we now know is

that the blood-brain barrier prevents a "charged" form of mercury (charged

because it has extra electrons) from crossing into the brain. The truth is, there's

simply no such thing as a "non-toxic" form of mercury, because once mercury

enters the body the enzyme catalase strips an electron or two from a charged form

of mercury (mercury chloride), creating an uncharged form (elemental mercury

vapor) that readily crosses the blood-brain barrier.85

Once mercury is in the brain, catalase will contact the mercury and charge it again,

and it will then be unable to exit the brain. Enter glutathione. The antioxidant

glutathione is the main detoxifier of mercury, and is itself a thiol (sulfur-containing

compound). About 80% of ingested mercury can potentially be excreted by

attaching to glutathione and exiting through the bowel. Unfortunately, we're

seeing that nearly every disease, including Parkinson's, involves glutathione

deficiency. This would be because of being used up by mercury, but also many

other toxic substances, like acetaminophen, as well as from a diet devoid in

nutrients necessary to make glutathione. One nutrient critically needed is sulfur,

which would most abundantly be obtained from a diet rich in cruciferous

vegetables. Bottom line is that without sufficient detox methods, like glutathione,

mercury is reabsorbed and continues doing damage.

As we will discuss more later, simply taking glutathione orally or even

intravenously doesn't appear to solve the problem. In bodies with damaged

mitochondria, and used up glutathione, there are elevated enzymes (attempting to

compensate for the lack of glutathione) that break down much of the attempt to

replenish glutathione. When glutathione breaks down, one of its component parts,

glutamate is released and contributes to the problems already in progress. Also as

discussed earlier, but it bears repeating, in a mercury-damaged brain, there is an

inhibition of glutamine synthetase (GS).86

Normally, glutamine synthetase

catalyzes the ATP-dependent condensation of glutamate with ammonia to yield

85 E Duhr, B Haley et al. Hg2+ Induces GTP-Tubulin Interactions in Rat Brain Similar to Those Observed in Alzheimer's Disease. Federation of American Societies for Experimental Biology (FESAB). 75th Annual Meeting. Atlanta, GA 21-25 April 1991. Abstract 493 86 JW Allen et al. Mercuric chloride, but not methylmercury, inhibits glutamine synthetase activity in primary cultures of cortical astrocytes. Brain Res (2001) 891, 148-157.

36 | P a g e

glutamine. In other words glutamine synthetase is crucial in recycling glutamate so

it doesn't build up and become "excitotoxic". Lack of glutamine synthetase

contributes to excess glutamate. Excess glutamate causes excess nitric oxide and

resultant highly toxic metabolites like peroxynitrite and has been proven to result

in the death of dopaminergic neurons.

Glutathione needs to get back an electron it has lost to be reactivated, and it has

been shown that vitamin C is critical in that process. A diet and supplement

regimen rich in vitamin C, as well as sulfur-containing foods and supplements have

been shown to elevate glutathione safely, abundantly, and better than taking

glutathione itself. A caution here before we continue. There are supplements like

whey protein (rich in sulfur proteins) that has been shown to elevate glutathione

levels. Unfortunately the supplement is "whey protein isolate" which is a source of

free glutamates, and therefore unsuitable for people with Parkinson's.

When damaged mitochondria spew out the reactive oxygen species hydrogen

peroxide, the main antioxidant to protect neurons is catalase87

(it functions to

"catalyze" hydrogen peroxide into water and oxygen).88

One molecule of catalase

can convert millions of molecules of hydrogen peroxide to water and oxygen per

second.89

Oral supplements are available for catalase as well some other

antioxidants produced naturally within the body (e.g., SOD and glutathione).

Unfortunately, taken orally, these antioxidants are merely broken down within the

intestine before they ever reach the cells that need them. Thus, consuming foods

rich in the building blocks required to make these natural antioxidants (manganese,

zinc, copper, and selenium) is a more effective way to increasing their levels in the

body. These trace elements are found abundantly in a diet made up of copious

quantities of whole, organic plant foods.

87 R Dringen et al. The glutathione system of peroxide detoxification is less efficient in neurons than in astroglial cells. J Neurochem (1999) 72, 2523-2530. 88 P Chelikani et al. Diversity of structures and properties among catalases Cell Mol Life Sci. 61 (January

2004) 2:192–208 89 DS Goodsell "Catalase". Molecule of the Month. RCSB Protein Data Bank. September 1, 2004.

37 | P a g e

But My Dentist Told Me Mercury Isn't Toxic

Ask most dentists if mercury is toxic, and the pat answer is often, "There is no peer

reviewed science linking mercury in an amalgam to any harm." The deception

here is in specifying "mercury in an amalgam". They skirt the truth because

mercury has been studied and proven toxic extensively, but not specifically from

amalgams which would basically require studying the people while they have the

amalgams in their mouths. Of course mercury itself has been linked to devastating

harm as we've discussed. To imply that mercury in amalgams is harmless is

irresponsible in the least and criminal at worst.

That said, in 1992 Vas Aposhian challenge-tested students at the University of

Arizona by giving them a mercury chelating agent (DMPS). He discovered that

those with the greater number of amalgam fillings had the greatest mercury

recovered in their urine, and the greater level of neurological problems.90

This is

one study that has obviously been ignored.

We also have to consider that currently dentists are not allowed to diagnose any

medical disorder, much less treat a medical disorder, such as mercury toxicity or

90 HV Aposhian et al. Urinary Mercury After Administration 2,3-dimercapto propane-1-sulfonic acid:

Correlation With Dental Amalgam Score. FESAB J (1992) 6(6):2472-2476.

Recent studies have shown that metals, including iron, copper, chromium and vanadium

undergo redox cycling, while cadmium, mercury and nickel, as well as lead, deplete

glutathione and protein-bound sulfhydryl groups, resulting in the production of reactive

oxygen species as superoxide ion, hydrogen peroxide, and hydroxyl radical. As a

consequence, enhanced lipid peroxidation, DNA damage, and altered calcium and

sulfhydryl homeostasis occur. Fenton-like reactions may be commonly associated with

most membranous fractions including mitochondria, microsomes, and peroxisomes.

Phagocytic cells may be another important source of reactive oxygen species in

response to metal ions. Recent studies have suggested that metal ions may enhance the

production of tumor necrosis factor alpha (TNFa) and activate protein kinase C, as well

as induce the production of stress proteins. Thus, some mechanisms associated with the

toxicities of metal ions are very similar to the effects produced by many organic

xenobiotics. Specific differences in the toxicities of metal ions may be related to

differences in solubilities, absorbability, transport, chemical reactivity, and the complexes

that are formed within the body. [S.J. Stohs and D. Bagchi. Oxidative Mechanisms in the

Toxicity of Metal Ions. Free Radical Biology & Medicine. Vol. 18. No. 2. pp 321-336, 1995]

38 | P a g e

any maladies arising from such a toxicity. If a savvy dentist suspects mercury

toxicity, he/she is supposed to refer the patient to their doctor or other healthcare

professional. The irony here, is that a dentist who fully understands the toxicity of

mercury would be the one who could safely remove amalgams, the source of the

mercury. Without the dentist's help, the patient is the one who is then left without

a solution to their health dilemma.

How Mercury Damages the Mitochondria

A 2008 study lists many of the diseases known to have mitochondrial dysfunction

at their core including diabetes, hyperlipidaemia, and hypertension. The

researchers wonder "How does a mutation in mitochondrial DNA lead to disease

at the cellular level, and how can a single mitochondrial DNA point mutation result

in such a variety of renal and non-renal phenotypes...and why are some regions of

the nephron seemingly more sensitive to mitochondrial dysfunction and damage by

mitochondrial toxins?"91

Perhaps they would find their answer if they simply

inserted mercury into the equation, that is, mercury's extraordinary affinity to

sulfur and the kidneys (rich in the aforementioned sulfur-rich microtubules).

Why, again, mercury? Why not equally assume the toxin is a pesticide? One

reason is that mercury does not break down into harmless substances, but

repeatedly does damage, causing widespread devastation throughout the body (this

damage is seen in mammals, plants, and insects). On the other hand, substances

like rotenone (an "organic" pesticide used to induce parkinsonism in lab animals)

does break down, quite easily, actually, by temperature, light oxygen and

alkalinity. Rotenone also breaks down by the universal solvent, water, and by

carbon.92

So you would have to deliberately encounter rotenone for it to be toxic.

91 Hall AM et al. Renal function and mitochondrial cytopathy (MC): more questions than answers? QJM

2008 Oct;101(10):755-766. 92 http://myfwc.com/newsroom/Resources/News_Resources_PiranhaFAQs.htm

39 | P a g e

As we discussed previously, some mercury can be eliminated from the body,

bound to an antioxidant sulfur molecule (like glutathione), but the remaining

mercury will come to "rest" deep within tissues, like in the bone.93

Mercury does its dirty work and then flees the scene, and this is why researchers

aren't instantly pointing the finger at the poison. By the time damaged cells and

tissues are studied, mercury is no longer necessarily hanging around at the scene of

the crime - the obvious culprit. This leaves all the damage that was done to be

studied and blamed.

Why is this all so important? Because mercury's devastating effects upon the

"energy factories" of our bodies is not being given the weight of acknowledgement

it merits, but is being "watered down" and lumped in with all the other potential

dangers to the neurological system. Thus, people in the 21st century are still lining

up for immunizations containing mercury. I cannot tell you how many times I've

heard people say, "but they've taken the mercury out". Wrong. Mercury

(thimerosal) is still in "multi-use" vials in 2010. A sign seen during 2009's "swine

flu vaccination" campaign said: "If you have an allergy to thimerosal, let us know."

An allergy? To a poison they aren't even honest enough to warn is really mercury?

In fact, if you give birth to a baby in 2010, that infant is most likely going to be

given a Hep B shot with 12.5 mcg of mercury the day it is born. Yet .1 mcg per

2.2 pounds of body weight is supposedly the "safe" limit per day.94

Watch closely,

because if you blink your eyes in the birthing room you'll miss it. It is often done

by a nurse while the infant is in the warmer, minutes after birth!

93 http://www.idph.state.il.us/envhealth/factsheets/mercuryhlthprof.htm 94

The Environmental Protection Agency (EPA).

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There is yet another tragedy occurring where mercury isn't given the villainous

credit it deserves. Kidney dialysis patients, Lupus patients and others with

autoimmune diseases are treated with "Immunoadsorption" to cleanse the blood

of "autoantibodies". A common practice is to use thimerosal (a mercury

compound) to prevent microbial growth in the equipment. Patients treated with

Immunoadsorption were found to have significantly elevated mercury levels.95

How ironic that the very thing that may have caused their disease in the first place

(it is said that approximately 80% of mercury is retained in the kidneys where it

"pokes holes" in tubules) is being carelessly used in their treatment.

Because mercury is brushed off as just "one of many" toxins that we "might"

encounter, people are eating fish filled with mercury (all fish have some level of

mercury due to environmental levels of mercury spewed from industry). We need

to keep in mind that the sale of seafood is a multi-million dollar industry, and

sellers of seafood will slant the facts to protect the sales. It is most important to

95 Ludwig Kramer et al. Mercury exposure in protein A immunoadsorption. Nephrol Dial Transplant

(2004) 19:451-456.

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consider the epidemic of neurological diseases today, and the mercury connection.

Thus, even a "low level" or "trace" of mercury is not acceptable, especially

considering all the other sources of mercury you might encounter daily.

(See chart of mercury in fish at www.maine.gov/dhhs/eohp/fish/hgposter.htm).

Another source of mercury are those new "long life" light bulbs, but also the

"fluorescent" bulbs that have been around for quite some time. How many are

broken and swept up by unsuspecting victims who breathe in the deadly mercury

vapor? Yet, because mercury isn't acknowledged for the widespread, internal,

nuclear-explosion damage it is causing, the government is actually considering

making those type of bulbs mandatory.

No question about it, mercury is the neurotoxic element that all Parkinson's

patients have in common now and in days gone by. Conversely, all do not

necessarily have in common rotenone, paraquat, methamphetamine, advanced age,

and the many other possible "causes" mentioned in the thousands of studies.

Master's degree candidate Laura A. Williams from University of Calgary, Canada

in her thesis writes: "Damaged DA neurons are afflicted with a mitochondrial

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malfunction possibly caused either by a genetic mutation or cytotoxic chemicals."96

The truth is, the cause of genetic mutations, and the cytotoxic chemical is likely

one and the same, and most often the highly toxic, highly ubiquitous, sulfur-loving

mercury. Coincidentally, the University of Calgary is also home of Professor,

Doctor Naweed Syed and colleagues who have filmed How Mercury Causes Brain

Neuron Degeneration (video available on You Tube) wherein they state that only

mercury caused a devastating denuding of the neurons (a depolymerizing of

tubulin which link together to form the neurite membrane)97

. It is the loss of

tubulin coating of the neurons that causes the neurofibrillary tangles seen in

neurological diseases, like Alzheimer's and Parkinson's. When the Calgary

researchers tried to cause the same damage to neurons with lead, cadmium,

aluminum or other metals, they did not get the same results. This aligns with other

researchers' observation that while lead, for example, has a definite deleterious

effect on the central nervous system, it apparently isn't due to having the same

degree of affinity for neurons as does mercury. In fact, researchers talk about the

"discordance between the low affinity of nervous tissue for lead, and this metals'

pronounced encephalopathic effect.98

Once again evidence shows that mercury is the most common toxin doing the

initial devastating damage, and that other metals, like lead, cadmium, nickel, even

the normally healthful iron and copper, will then participate in the devastating

oxidative stress that accompanies mercury's "fallout".

Mercury and Complex I of the Mitochondria

In a 2009 study in Molecular Neurodegeneration researcher Charles R Arthur et al

state: Sporadic Parkinson's disease brain mitochondria have reduced mitochondrial

respiratory protein levels in complexes I-V, implying a generalized defect in

respirasome (a basic unit for respiration) assembly. Damage to the mitochondrial

electron transport chain in turn causes increase in nitric oxide, lipid

96 Laura A. Williams, Bioprocessing of Human Embryonic Stem Cells for the Treatment of Parkinson's Disease. A Thesis. Dept of Chemical and Petroleum Engineering. Calgary, Alberta. April, 2008. 97 DDW Leong, NI Syed et al. Retrograde Degeneration of Neurite Membrane Structural Integrity of

Nerve Growth Cones Following in vitro Exposure to Mercury NeuroReport (2001)Vol 12 No 4 98 Sternlieb I, Goldfischer S. Heavy metals and lysosomes. Front Biol. 1976;45:185-200.

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peroxidation, and glutathione depletion.99

Arthur et al did not find any

"downstream etiologies", and surmise that the damage may indicate a unique

consequence of aging7.

Szeto goes on to explain that recent studies show that Complex I releases O2- into

the mitochondrial matrix, while complex III can release O2- into the matrix but also

across the intermembrane space. Once there, superoxide anion is then converted to

H2O2 by the mitochondrial matrix enzyme MnSOD or by CuZnSOD. Being more

stable, H2O2 can diffuse out of the mitochondrion and into the cytosol. In the

presence of transitional metals (like iron and copper complexes found in the inner

membrane) H2O2 can be converted into the highly reactive hydroxyl radical OH-.

O2- can also react with nitric oxide to form the highly reactive peroxynitrite

ONOO-. The highly toxic peroxynitrite anion destroys cellular

macromolecules100

and reacts rapidly with thiols.101

Another study looking for the source of all these reactive oxygen species in the

brain uncovered mercury as the source. They showed that mercury inhibits CoQ10

(ubiquinol) cytochrome c oxidoreductase region, which is complex III of the

mitochondrial electron transport chain.102

The mostly commonly studied reactive oxygen species (which includes reactive

nitrogen species) are hydrogen peroxide (H2O2), superoxide (O2-), hydroxyl

99 Jose LM Madrigal et al. Glutathione Depletion, Lipid Peroxidation and Mitochondrial Dysfunction Are

INduced by Chronic Stress in Rat Brain. Neuropsychopharmacology. (2001) 24. 420-429. 100 Katalin Sas et al. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system,

with focus on neurodegenerative disorders. Journal of the Neurological Sciences 257 (2007) 221-239. 101 Madia Trujillo and Rafael Radi. Peroxynitrite Reaction with the Reduced and the Oxidized Forms of

Lipoic Acid: New Insights into the Reaction of Peroxynitrite with Thiols. Archives of Biochemistry and

Biophysics (Jan 2002) Vol 397, Issue 1. 1 91-98. 102 S Yee & BH Choi. Oxidative stress in neurotoxic effects of methylmercury poisoning. Neurotoxicology 17 (1996) 17-26.

Oxygen normally serves as the ultimate electron acceptor and is reduced to water.

However, electron leak to oxygen through complexes I and III can generate superoxide

anion O2-. [Hazel H. Szeto. Mitochondria-Targeted Peptide Antioxidants: Novel

Neuroprotective Agents. The AAPS Journal 2006;8(3) Article 62. E522-E531.

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radicals (OH-), nitric oxide (NO), peroxynitrite (ONOO

-) and hypochlorus acid

(HOCl). These molecules can and do rapidly convert to even larger reactive

intermediates that are even more dangerous and difficult to neutralize in the body.

Again, this is absolutely critical, because if we're going to stop the mess, we're

going to have to aim our therapies at the mitochondria where the damage first

occurs, and the oxidative chain reaction begins!

With what we know about mercury's affinity for the mitochondrial membrane, can

we at least make sure we don't jump through hoops with mitochondrially-targeted

therapies and then continue to offer our patients immunizations with mercury?

Indeed, what do a 10 year old, a 30 year old (like Michael J Fox) and a 65+ year

old all have in common? Regular exposure to mercury! For centuries people have

aged without getting Parkinson's. Debilitating neurological diseases are just not a

part of the "Master Plan", and neither is the deliberate ingestion of mercury.

Reactive Oxygen Species From Damaged Mitochondria

Damage to the mitochondria's electron transport chain results in continuous

oxidative stress. It is a vicious cycle, unable to be broken due to antioxidant

systems that normally keep reactive oxygen species under control. Thus, the

problem is the imbalance between production and removal of reactive oxygen

species. Again, reactive oxygen species are defined as any species capable of

independent existence that contains one or more unpaired electrons.103

During normal physiological reactions occurring in a healthy body, reactive

oxygen species such as O2-, nitric oxide, and hydrogen peroxide perform beneficial

functions before being neutralized by antioxidants. It is when they are produced in

abundance, unchecked, or transform into highly aggressive free radical species that

extensive cellular damage occurs. One such aggressive free radical is produced

when hydrogen peroxide converts to the highly reactive hydroxyl radical (OH-).

This reaction is usually catalyzed by iron. Another aggressive oxidant is

peroxynitrite (ONOO-). Peroxynitrite occurs in the body when O2

- reacts with

103 Halliwell B and Gutteridge J.M.C. Free radicals in biology and medicine. Oxford University Press,

Oxford, New York. 2007.

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nitric oxide104

, both of which are produced in abundance by damaged

mitochondria.

Oxidative stress induces cytotoxicity by damaging DNA, proteins and lipids. In

DNA damage, strands break, crosslinkages between DNA-DNA or DNA-protein

and errors in DNA replication occur, and can also lead to tumor formation.105

Oxidative stress is seen in Parkinson's and other neurological diseases as oxidative

damage occurs to proteins resulting in protein-protein cross-linking,

fragmentation, and "folding" if the side chains of the molecule are affected.106

All from mercury, you say? Could one single poison be affecting so many people

today? Well, it just so happens that also during the aforementioned Roman Empire

the people decided to make their entire waterways out of lead. They used lead for

cups and cooking pots and for vessels to make their wine. Josef Eisinger107

estimated that a Roman consuming a liter of wine a day would consume about 20

mg of lead, which he said was more than enough to produce chronic lead

poisoning. Ever heard of the "Fall of the Roman Empire"? What do you suppose

would happen to a civilization wherein every single resident consumed lead on a

daily basis? And yet to this day, this is debated! The infertility of the women that

resulted from lead ingestion, for example, is often surmised to have been merely

from a desire to not have any children. I suggest we continue with eyes wide

open, and know that if everyone in a society ingests a known poison continuously,

it can, indeed, poison everyone.

So before you grow weary of the emphasis on mercury, let me perhaps amuse you

with an analogy. Consider that there are many ways to "die in a crash". It can be

an airplane crash, a train crash, a boat crash or an automobile crash. And just as

statistics show you are most likely to die in an automobile crash, we are finding

104 P. Pacher et al. Nitric Oxide and Peroxynitrite: in Health and disease. Physiological Reviews 2007, Vol

87(1) 315-424. 105 UA Boelsterli. Mechanistic Toxicology: The molecular basis of how chemicals disrupt biological targets (2003) New York: Taylor & Francis 106 PD Josephy. Molecular Toxicology (1996) New York: Oxford University Press 107 Josef Eisinger. "Lead in History and History in Lead" (1984) Nature Publishing Group.

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that mercury is the most likely vehicle causing the "crash" in neurological (and

many other) diseases today.

Mercury And The Brain's Immune System

Let's talk a little bit about the cells that make up the brains immune system. Within

the brain (in addition to neurons) are glial cells (also called neuroglia or glia).

Glial cells support and protect the brain's neurons. There are about three glial cells

for every neuron in the gray matter of the brain (which is where neurons reside -

compared to white matter which mostly contains myelinated axon tracts).108

Glial

cells surround neurons and hold them in place, supply nutrients and oxygen to

neurons, insulate one neuron from another, and orchestrate neurotransmission.

Glial cells also act as the brain's "immune system" by destroying pathogens and

removing dead neurons.109

Astrocytes (also known as astroglia) are star-shaped glial cells in the brain and

spinal cord. They perform many unique functions of their own, including support

of endothelial cells which form the blood-brain barrier. Because the job of the

blood-brain barrier is to keep harmful or foreign molecules out of the brain, as you

can see, it is an important part of the brain's immune system.

Research since the mid-1990s has shown that, similar to neurons, astrocytes release

transmitters (called gliotransmitters) in a Ca2+

-dependent manner. It is thought that

astrocytes signal to neurons through Ca2+

-dependent release of glutamate which

has now made astrocyte research of even more interest to neuroscientists. 110

Then there are the antioxidants that are designed to protect the brain from oxidative

damage. Glutathione is the main antioxidant protecting the brain from reactive

oxygen species. Glutathione is a thiol, i.e., an organosulfur compound (contains

a sulfur-hydrogen bond). There needs to be enough of the amino acid cysteine to

manufacture glutathione. Cysteine is also a thiol. Cysteine is considered a non-

essential amino acid because it is synthesized within the healthy body if there is

108 Dale Purves et al. Neuroscience 4th ed (2008) Sinauer Associates 15–16. 109 H Wolosker et al. d- Amino acids in the brain: d-serine in neurotransmission and neurodegeneration.

FEBS J (2008 Jul) 275(14):3514-26. 110 TA Fiacco et al. "Sorting out Astrocyte Physiology from Pharmacology". Annu Rev Pharmaco. Toxicol

(October 2008) 49:151

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enough of the essential amino acid methionine. An essential amino acid means it

must be obtained from the diet.

Methionine synthesizes some other nutrients in the body like the amino acid

taurine, the phospholipid lecithin, and phosphatidylcholine (a phospholipid that

makes up healthy cell membranes). Healing foods that are rich in methionine are

sesame seeds, brazil nuts, garbanzo beans, corn, almonds, lentils and brown

rice. If you are looking to boost methionine levels in your diet, however, look to

the raw nuts and seeds above the lentils or rice, unless you sprout them and eat

them raw. The reason for this is that cooking alters nutrients. With proteins, I like

to use an egg as my standard for judging proteins/amino acids. Consider the

appearance of a raw egg versus a cooked egg. The difference in appearance has to

do with the fact that when you cook the egg you coagulate the protein and oxidize

the fats. The white turns from clear to opaque. The yolk turns from bright yellow

to an ashen gray yellow, and smells of sulfur that was released by the cooking.

Of interest, too, is that methionine is converted to S-adenosylmethionine (SAMe)

by methionine adenosyltransferase. SAMe acts as a methyl-donor in many

methyltransferase reactions in the body. Methyltransferase reactions are

performed in wide variety of biological functions in the body from DNA

methylation in an early embryo's development to recycling amino acids like

methionine. Along the pathway for methionine, homocysteine is formed.

Homocysteine is actually a homologue (has a similar chemical formula) to

cysteine, and is seen elevated in cardiovascular disease and Parkinson's.

Homocysteine can be recycled back into methionine, but to do so, the body uses

Vitamin B12 (cobalamin)-related enzymes. In addition, there needs to be enough

folic acid (Vitamin B9) and Pyridoxine (Vitamin B6).111

Trimethylglycine (a

betaine) is also a methyl donor, and has been shown to reduce homocysteine levels

in blood.112

111 JW Miller et al. "Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine

loading in rats". American Journal of Clinical Nutrition 59 (1994) (5):1033–1039. 112 DA Coen et al. "Homocysteine-lowering treatment: an overview". Expert Opinion on

Pharmacotherapy 2 (2001) (9):1449–1460.

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How does this all relate to the brain's immune system? Remember, the immune

system you are familiar with protects your cells from damage from foreign

invaders, like parasites but also mercury. Likewise, it has been shown that

astrocytes release glutathione to generate a dipeptide CysGly (cysteinyglycine)

which is then used by neurons as the precursor for their glutathione synthesis.

Glutathione, of course, is the main detoxifier of mercury in the brain. In fact, in

one study incubating neurons with astroglial cells resulted in neuronal glutathione

levels twice that of neurons incubated without astroglial cells.113

Astrocytes have

been shown to be more resistant to cytotoxicity than neurons.114,115

Why are

astrocytes more resistant to cytotoxicity than neurons? It has been shown that

excess glutamate can impair the Na+-dependent cysteine transporters

116 which

would lead to deficiencies in glutathione in neurons, which would make neurons

less capable of detoxifying reactive oxygen species by the glutathione pathway.

Interestingly, chronic methyl mercury exposure in humans showed a loss of

neurons, and a proliferation of astrocytes.117

In his Master's thesis exploring the demethylation of methylmercury in the central

nervous system, Aaron Shapiro explains how inorganic mercury and methyl

mercury are both toxic, just through different mechanisms. He outlines studies

showing how inorganic mercury preferentially target astrocytes, while methyl

mercury targets neurons. Because inorganic mercury does not penetrate the blood-

brain barrier, he concludes that the presence of inorganic mercury in the brain after

orally administered methyl mercury can only be explained by demethylation in

situ. He points to studies that show that demethylation occurs in the brain, driven

113 Ralph Dringen et al. Synthesis of the Antioxidant Glutathione in Neurons: Supply by Astrocytes of

CysGly as Precursor for Neuronal Glutathione. The Journal of Neuroscience (Jan 15, 1999) 19(1):562-569. 114 JW Allen et al. Mercuric chloride, but not methylmercury, inhibits glutamine synthetase activity in primary cultures of cortical astrocytes. Brain Res 891 (2001) 148-157. 115 R Dringen et al. The glutathione system of peroxide detoxification is less efficient in neurons than in astroglial cells. J Neurochem 72 (1999) 2523-2530. 116 JW Allen et al. The consequences of methylmercury exposure on interactive functions between astrocytes and neurons. Neurotoxicology, 23, (2002)755-759. 117 K Eto et al. Differential diagnosis between organic and inorganic mercury poisoning in human cases—the pathologic point of view. Toxicol Pathol 27 (1999) 664-671.

49 | P a g e

by oxidative stress. He said it would be "reasonable to assume" that mitochondrial

reactive oxygen formation contributes to methyl mercury demethylation.118

As we mentioned, optimal levels of glutathione can be maintained in astrocytes

under oxidative stress conditions if there are enough glutathione precursors (sulfur

amino acids) and vitamin C.119

Mercury And The Viral Connection

Many diseases are shown to have a "viral component", so much so, that researchers

often assume it is the virus that caused the disease in the first place. The truth is,

viruses live dormant in nerve ganglia. When an opportune time arrives, viruses

leave the ganglia to travel along nerves to swoop in and invade damaged cells .

Healthy cells build up defenses against viruses while damaged cells are completely

vulnerable to infection. The entire purpose for a viruses' existence is to replicate.

When they move into cells to do this, they kill the cell in the process.

Mercury damages cells, and has been shown to increase mortality due to viral

infections.120

Mercury has been found repeatedly to accumulate in

macrophages121,122

interfering with macrophage functions in the body that control

viral replication leading to advanced viral infections.123

Injected mercury shows up accumulated in organs, including organs of the immune

system, which include the spleen, thymus, lymph nodes and bone

118 Aaron Shapiro B.Sc., University of Guelph. Characterization of Methylmercury Demethylation In The

Central Nervous System. (2005) Thesis Submitted in Partial Fulfillment Of The Requirement For The

Degree Of Master Of Science In Interdisciplinary Studies. (January 2008) The University of Northern

British Columbia. 119 E O'Connor et al. Biosynthesis and maintenance of GSH in primary astrocyte cultures: role of L-cystine

and ascorbate. Brain Research (1995) Vol 680 Issues 1-2. 157-163. 120 LD Koller Methylmercury: effect on oncogenic and nononcogenic viruses in mice. Am J Vet Res 36, (1975)1501–1504. 121 YM Sin et al. Effect of lead on tissue deposition of mercury in mice. Bull Environ Contam Toxicol 34, (1985) 438–445. 122 M Christensen et al. Histochemical and functional evaluation of mercuric chloride toxicity in cultured macrophages. Prog Histochem Cytochem 23, (1991) 306–315. 123 S Ellerman et al. Effect of mercuric chloride on macrophage-mediated resistance mechanisms against infection with herpes simplex virus type 2. Toxicology 93, (1994)269–87.

50 | P a g e

marrow.124,125,126,127

In a study to estimate the toxicity of mercury, electron

microscopy showed that the mercury accumulated mostly in the lysosomes of

macrophages and endothelial cells. Their study showed that the bone marrow

showed only a few grains of mercury, found in cells "with macrophage

appearance".128

Lysosomes are organelles (recall that mitochondria are also organelles).

Lysosomes contain enzymes (acid hydrolases) that disassemble waste materials

and cellular debris within the cell, including other worn-out organelles, food

particles, and engulfed viruses or bacteria (engulfed by macrophages).

Some Other Toxins That Have Been Shown To Cause Parkinsonism

Contrast mercury, now, with other toxins that are said to produce Parkinson's (used

mostly in lab animals and injected directly into the animal) like paraquat, first

synthesized in 1882, but not used commercially until 1961129

; or amphetamine,

which was first synthesized in 1887 but not really used until 1927130

. It's not that

we discount these possible toxins, but that we be realistic about the epidemic of

Parkinson's, and just what toxin(s) Parkinson's patients are most likely to be

exposed to, and have in common, especially for all these years since the "Shaking

Palsy" was first documented centuries ago. If you start to get confused, referred

back to the CERCLA list, and how it is generated, especially the part about its

potential for human exposure.

124 M Mehra & KC Kanwar. Clearance of parenterally administered 203Hg from the mouse tissues. Jepto

5-4/5 (1984) 127-130. 125 JK Nicholson et al. Comparative distributions of zinc, cadmium and mercury in the tissues of

experimental mice. Comp Biochem Physiol B 77 (1984) 249-256. 126 F Planas-Bohne et al. The influence of administered mass on the subcellular distribution and binding

of mercury in rat liver and kidney. Arch Toxicol 56 (1985) 242-246. 127 JB Nielsen & O Andersen. Disposition and retention of mercuric chloride in mice after oral and

parental administration. J Trace Elem Electrolytes Health Dis 30 (1990) 167-180. 128 M. Christensen. Histochemical localization of autometallographically detectable mercury in tissues of

the immune system from mice exposed to mercuric chloride. Histochemical Journal 28 (1996) 217-225. 129 http://www.inchem.org/documents/ehc/ehc/ehc39.htm Paraquat and Diquat 130 L. Edeleanu. Uber einige Derivate der Phenylmethacrylsaure und der Phenylisobuttersaure. Ber

Duetsch Chem Ges 1887;Vol 20:616.

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That said, many other potential toxins aren't normally encountered to the degree

mercury is, but all must be considered. Of course, you might be right in suspecting

something other than just mercury if you live in Somerville, Texas, where nearly

every single resident suffers everything from birth defects to bladder, pancreatic or

brain cancer from a massive wood-treatment facility, which for more than 100

years has churned toxic chemicals into the atmosphere while manufacturing phone

poles and bridge supports. But then, mercury has been used historically for

preserving wood. Were they using it in Somerville?

While we must first condemn mercury, and do so quickly, because it is deliberately

being injected, implanted and eaten on a daily basis, we must also consider the

other neurotoxins that have been shown to induce Parkinson's as well.

OHDA In "Tyrosine Hydroxylase Gene Transfected Hematopoietic Stem Cells in

a rat model of Parkinson's disease", they say that dopamine levels were restored in

46.6% and 33% of control. They say the transferred cells showed excellent

survival rates in PD rat brains, and distant migration was observed. The toxin used

to induce the Parkinson's? The rats were injected with 8 micrograms of 6-

OHDA.131

6-OHDA is oxidized dopamine.

So would we observe the same success with a tyrosine hydroxylase gene

transfected hematopoietic stem cell transplant in a human with Parkinson's? So far

it appears that Parkinson's in humans involves widespread damage to

mitochondria and resultant loss of glutathione along with the generation of reactive

oxygen species that ultimately does to transplanted hematopoietic stem cells what

normally occurs in the Parkinson's patient, that is, damage to any new

dopaminergic neurons.

Before we go on, we need to discuss the mitochondrial electron transport chain

(ETC). The ETC occurs in the mitochondrial membrane, and is what we're now

seeing is damaged leading to a cascade of events, all of which are seen in

Parkinson's. Complex I (NADH Dehydrogenase) is the first enzyme of the

mitochondrial electron transport chain. Complex I translocates four protons per 131 Shizhong Zhang et al. The Therapeutic Effects of Tyrosine Hydroxylase Gene Transfected

Hematopoietic Stem Cells in a Rat Model of Parkinson's Disease. Cell Mol. Neurobiol (2008) 28:529-543.

52 | P a g e

one oxidized NADH across the inner mitochondrial membrane, thus participating

in the building of adenosine triphosphate which is the "energy" molecule of the

mitochondria. Mutations in the subunits of Complex I can cause mitochondrial

diseases, and as we've said, Parkinson's now appears to be first and foremost, a

mitochondrial disease. Recent studies have shown that cell lines with Parkinson's

disease show increased proton leakage in Complex I, which causes decreased

maximum respiratory capacity.132

It would be noteworthy here to mention that you will find experts who have listed

the very same diseases as the Mattson study as being "caused by mercury". It

might be a good time to consider where other toxins are also known to induce

Parkinsonism.

Rotenone is an organic pesticide. "Organic" because it is an isoflavonoid

obtained from a tropical plant. However, rotenone can induce Parkinsonism

because it is an inhibitor of Complex I. Rotenone binds to the ubiquinone (CoQ10)

binding site of Complex I, thus interfering with ATP production. But to induce

Parkinson's in animals, a syringe full of rotenone is injected into the animal. The

same goes for another chemical called Paraquat.

Paraquat is an herbicide, widely used throughout the world. Because it has

been shown to induce Parkinson's symptoms, it has become one of the toxins of

choice in study models of Parkinson's.

132 Esteves AR et al (February 2010). "Mitochondrial respiration and respiration-associated proteins in

cell lines created through Parkinson's subject mitochondrial transfer." Journal of Neurochemistry 113

(3): 674–82

"Mitochondria-mediated oxidative stress, perturbed Ca2+ homeostasis and apoptosis may

also contribute to the pathogenesis of prominent neurological diseases including

Alzheimer's, Parkinson's and Huntington's diseases, stroke, ALS and psychiatric

disorders. Advances in understanding the molecular and cell biology of mitochondria

are leading to novel approaches for the prevention and treatment of neurological

disorders. [Mark P. Mattson et al. Mitochondria in Neuroplasticity and Neurological

Disorders. Neuron. 2008 December 10;60(5):748-766.

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Paraquat appears to contribute to the generation of reactive oxygen species via

mitochondrial damage, imbalances or dysfunction. When O2 is present, paraquat

generates superoxide in high amounts which is what accounts for its toxicity. In

fact, it is due to this toxic level of reactive oxygen species that paraquat inhibits

photosynthesis and Co2 fixation in plants, killing the plant.

Some studies show that complex I of the respiratory chain is the main site of

superoxide production by paraquat. Paraquat PQ2+

undergoes univalent reduction

to generate the paraquat radical which then reacts rapidly with O2 to produce

superoxide.133

Other studies point to Complex III as the potential site of paraquat's

toxic action. Whatever the case, paraquat exposure has been identified in

epidemiological studies as well as in toxicant-based models of Parkinson's, points

to the importance of mitochondrial damage and reactive oxygen species as that

which leads to dopaminergic cell death, and thus Parkinson's.

Paraquat rapidly depletes glutathione and protein thiols, induces lipid peroxidation

and its cytotoxicity is related with the uncoupling of oxidative phosphorylation in

the mitochondria.134

Superoxide dismutase (SOD) is capable of inhibiting the

actions of paraquat.135

MPTP used to induce Parkinson's in studies with animals, has provided several

insights on the potential role of mitochondrial complex I dysfunction in PD

pathogenesis.136

In fact, there are other even more potent complex I inhibitors

(paraquat, rotenone, pyridaben, and fenpyroximate) which, when administered at

even low doses have been shown to produce symptoms like Parkinson's, and lead

133 Helena M. Cocheme and Michale P. Murphy. The uptake and interactions of the redox cycler

Paraquat with mitochondria. Methods in Enzymology Vol 456. 2009. pp 395-417. 134 Carols M. Palmeira et al. Thiols metabolism is altered by the herbicide paraquat, dinoseb and 2,4-D: A

study in isolated hepatocytes. Toxicology Letters Vol 81, Issues 2-3, 15 November 1995, Pages 115-123. 135 B.J. Day et al. A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced

endothelial cell injury, in vitro. J Pharmacol Exp Ther 275, 1227-1232. 136 Przedborski S et al. MPTP as a mitochondrial neurotoxic model of Parkinson's disease. J. Bioenerg

Biomembr 2004;36:375-379.

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to neurodegeneration.137,138

Many potential toxins, but one underlying issue:

Damaged and thus dysfunctional mitochondria.

The Acetogenin Family of Compounds are the most potent Complex I

inhibitors. Some compounds in this family that the average person might

encounter are erythromycin A, Azithromycin, amphotericin, and tetracyclines -

all are antibiotics or antifungals.

Aerotoxic Syndrome There is also something few people know about called

Aerotoxic Syndrome. Engine oil leaks fill the cabin air with fumes. One pilot

who experienced this firsthand relates, "During the descent my first officer

complained he was feeling very sick. He needed to put his oxygen mask on. A

couple of seconds later I felt so bad I was ready to throw up all over the instrument

panel." The pilots donned oxygen masks, but spent the next few minutes

paralyzed. So what happened?

With all modern aircraft the outside air is compressed and heated by the jet

engines. The technical term for this is "bleed air". But there are no filters in the

system, therefore it is possible that the breathing air becomes contaminated with

heated engine oil, especially when maintenance is an issue, or if a seal starts to leak

or fail completely. This happens more often than airlines would like to admit. The

cockpit and the pilots get 100 percent bleed air. Flight attendants and passengers

in the cabin usually only get 40 to 60 percent of this air which is then recirculated.

Pilots have become ill and are now unable to fly. Susan Michaelis is a former pilot

for an Australia airline. She says this problem is a massive cover-up. She has

written a book where she documents hundreds of cases.139

Organophosphates Investigations have turned up the reason this is a

problem. Oil residue from modern jet engines contain numerous chemicals.

137 Betarbet R et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat

Neurosci 2000;3:1301-1306. 138 Derek A. Drechsel and Manisha Patel. Differential contribution of the mitochondrial respiratory chain

complexes to reactive oxygen species production by redox cycling agents implicated in parkinsonism.

ToxSci Advance Access Oxford University Press, September 18, 2009. 139 Captain Susan Michaelis, Editor. Aviation Contaminated Air Reference Manual. 2007.

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Organophosphates used as anti-wear agents. Among the ingredients is a

powerful neurotoxin, tricresyl phosphate, or TCP. There is up to 5% TCP in the

special high performance oils. Professor Chistiaan van Netten is a toxicologist at

the Canadian University of British Columbia, and an expert on TCP. He warns

that TCP in humans interferes with the electrical conduction within the nervous

system and consequently paralyzes people. In fact, in the 1920s, Jamaican ginger,

a prohibited alcoholic beverage, was tainted by TCP. Many people suffered

serious or fatal neurological damage.

The way TCP causes neurological damage is by inhibiting the enzyme

acetylcholinesterase leading to a buildup of acetylcholine in the synapses between

neurons. This ultimately leads to hyperactivity and death of the neurons.140

Karen Burns, a former stewardess, lost her health after just one flight. This was

because the cabin of her plane was filled with TCP. Now, she and two of her

coworkers suffer from serious nervous system effects, and Parkinson's-like

symptoms.

140 M. Mumtazuddin Ahmed and P. Glees. Neurotoxicity of tricresylphosphate (TCP) in slow loris. ACTA

Neuropathologica. (1971) Vol 19, No 2, 94-98

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ALL THE "THINGS GOING ON" IN PARKINSON'S

TRACE BACK TO MITOCHONDRIAL DYSFUNCTION

Iron And Copper - Causal Or A Result?

Some researchers are looking at iron and copper as possible causal factors in

Parkinson's. But limiting the ingestion of iron and copper from whole foods likely

does little to alter iron or copper "behaving badly" in the brains of healthy people.

Similarly, the trace amounts found in a natural, whole plant foods diet are not

something that can or should be avoided by people even with neurological

diseases! Indeed, Nature has put iron and copper in trace amounts in food for a

purpose. In fact, the brain is naturally rich in iron. It is reported that iron

deficiency is the most prevalent nutritional problem in the world today, with up to

5 billion people affected.141

However, taking iron supplements is a different story. Studies have shown an

almost two-fold increase in Parkinson's patient who took daily iron supplements.142

With what we now know about mitochondrial damage, the iron supplements did

not cause Parkinson's, of course, but can play a key role in the progression of the

disease once in progress. This would be akin to the fact that systems are damaged

to handle the body's natural manufacture and handling of glutamate. Consuming

free glutamates in the diet also play a key role in the progression of the disease.

Undeniably, iron overload is seen in many neurological diseases, including

Parkinson's. Excess iron has been associated with brain lesions, also seen in

neurological diseases. In addition, the excess iron has been associated with the

toxicity of mercury and other metals in the brain.143

Parkinson's disease, in fact, is

141 John Beard. Iron Deficiency Alters Brain Development and Functioning. The Journal of Nutrition. 2003

Supplement. 142 KM Powers et al. Parkinson's disease risks associated with dietary iron, manganese and other nutrient

intakes. Neurology (2003) 60:1761-1766. 143 Miyasaki K et al. Hemochromatosis associated with brain lesions - a disorder of trace metal-binding

proteins and/or polymers? J Neuropathol Exp Neurol. 1977 Nov;36(6):964-976.

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characterized by specific brain lesions (areas of damage) found in substantia nigra

and other subcortical nuclei, namely Lewy bodies, made up of aggregates of alpha-

synuclein. a-synuclein functions, in part, to regulate dopamine transporter

activities.

Recently, researchers have found that where there is accumulation of a-synuclein,

there is a decrease in Complex I activity in the mitochondria in Parkinson's disease

brains.144

In a 1986 study "Iron, A New Aid in the Treatment of Parkinson Patients"

Birkmayer and Birkmayer state: "Intravenously applied iron - in form of a ferri-

ferro-complex exhibited a considerable benefit for all (Parkinson's) patients treated

so far. They regained a remarkable mobility". 145

This would suggest, of course,

that iron is actually deficient because of a damaged mitochondria's inability to

"traffic" it properly.

Of course metal ions do participate in oxidative stress seen in Parkinson's and other

neurodegenerative diseases. In fact, metal ion chelators have shown therapeutic

value in ameliorating oxidative stress. The safest chelators, however, appear to be

dietary chelators which have been shown to negate and even reverse the role of

metal ions in oxidative stress.146

These dietary chelators are included in the

supplements and diet sections.

Indeed, the mitochondria is a "trafficker" of iron, or as some have put it, the

mitochondria is not just about energy transduction, but it is also a focal point of

iron metabolism.147

When the mitochondria is damaged, iron would be trafficked

improperly, would elevate where it normally does not belong, and would

144 Devi et al. Mitochondrial import and accumulation of a-synuclein impair complex I in human

dopaminergic neuronal cultures and Parkinson disease brain. Journal of Biological Chemistry, 283, 9089-

9100. 2008. 145 Birkmayer and Birkmayer. Iron, a New Aid in the Treatment of Parkinson Patients. J Neural Transm

(1986) 67: 287-292 146 Theresa Hague et al. Dietary chelators as antioxidant enzyme mimetics: implications for dietary

intervention in neurodegenerative diseases. Behavioural Pharmacology (2006) 17:425-430. 147 Richardson DR et al. Mitochondrial iron trafficking and the integration of iron metabolism between

the mitochondrion and cytosol. Proc Natl Acad Sci USA. 2010 Jun 15;107(24):10775-82.

58 | P a g e

participate in oxidative reactions. Here again we can see that it is the underlying

problem of mitochondrial damage leading to excess iron that needs to be

addressed.

Frataxin is a protein that in humans is encoded by the FXN gene. Frataxin is

found in the mitochondrion. When frataxin homologue YFH1 is missing in yeast

strains, there is an accumulation of iron in the mitochondria which then damages

the mitochondria. 148

When frataxin is mutated, there is iron overload. In deficiency of frataxin/YFH1,

researchers have identified 14 proteins which are selectively oxidized as well as

decreased superoxide dismutase activity, which promotes protein oxidative damage

as seen in neurological diseases. The addition of copper and manganese to the

culture medium restored SOD activity, preventing both oxidative damage and

inactivation of magnesium-binding proteins. Recovery of mitochondrial enzymes

required the addition of manganese, and cytosolic enzymes were recovered by

adding copper. It is the reduced SOD activity that contributes to the toxic effects

of iron accumulation.149

In a 2009 study from the University of Washington, researchers report on the

mutations and deletions in the mitochondrial genome saying the losses in stability

correlate with a reduction in the mitochondrial membrane potential. They state

that analysis of cells undergoing this instability showed a defect in iron-sulfur

cluster biogenesis, which requires normal mitochondrial function.150

This is

certainly not the only study to find that defects in the biogenesis of iron-sulfur

clusters arise as a consequence of mitochondrial dysfunction, and that this

increases genetic instability.

148 Francoise Foury and Driss Talibi. Mitochondrial Control of Iron Homeostasis - A Genome Wide

Analysis of Gene Expression Yeast Frataxin-Deficient Strain. JBC Papers December 8, 2000.

foury@fysa.ucl.ac.be 149 Irazusta V et al. Yeast frataxin mutants display decreased superoxide dismutase activity crucial to

promote protein oxidative damage. Free Radic Biol Med 2010 Feb 1;48(3):411-420. 150 Veatch JR et al. Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur

cluster defect. Cell 2009 Jun 26;137(7):1247-58.

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A 2010 study was done to determine the mechanisms of iron exit from the "ferritin

cage" in the mitochondria. Ferritin is a protein found inside of cells that stores iron

and releases it as needed. The researchers describe how twenty-four subunits of

ferritin combine to form a circular protein cage around up to 4,500 atoms of iron.

They say that there are two models with regard to how iron exits the ferritin cage,

and is reutilized. The first model has to do with the lysosomes degrading the

protein ring causing iron to exit, and the second model has to do with "pores" at the

junctures where the ferritin proteins join to create the ring, and iron being released

through those pores. The study says that some of the fundamental functions of iron

protein are still unclear. They say "...it is not known how cytosolic ferritin is

degraded, how stored iron is released." They do point to increased protein

degradation, and that blocking protein degradation prevented iron mobilization

from cytosolic ferritins. With regard to excess iron being released, we know that

mercury degrades proteins. Nowhere in the study is mercury mentioned, however.

With regard to a normal biological amount of iron being released, it appears

lysosomes may very well do the job of controlled protein degradation in order for

the iron to release.151

So it isn't that iron is a toxin like mercury to be avoided or eliminated at all costs.

It is that damaged mitochondria leads to a "misdistribution" of iron. A 2010 study

sums it up: "Iron concentrations can rise to toxic levels in mitochondria of

excitable cells". They say "iron chelation is probably inappropriate for

disorders associated with misdistribution of iron within selected tissues or cells."152

Iron would most definitely appear to be a result of Parkinson's, not a cause.

Not Simply A Dopamine Deficiency

Earlier I said that Parkinson's is no longer best defined as simply a dopamine

"deficiency". A damaged mitochondria results in toxic elements that cause

151

Yinghui Zhang et al. Lysosomal Proteolysis Is the Primary Degradation Pathway for Cytosolic Ferritin and

Cytosolic Ferritin Degradation Is Necessary for Iron Exit. Antioxidant & Redox Signaling (2010) Vol 13, No 7. 999-

1009.

152 Kakhlon O et al. Iron redistribution as a therapeutic strategy for treating diseases of localized iron

accumulation. Can J Physiol Pharmacol. 2010 Mar;88(3):187-96.

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dopaminergic neurons to die. Because most doctors don't seem to know that

Parkinson's is not just a "dopamine deficiency" the patient goes to neurologist and

gets a prescription for L-dopa/Carbidopa and little more. The doctor doesn't even

mention the mitochondria, doesn't ask about the patient's history with mercury,

pesticides or glutamates, or any other toxin for that matter, and may even give the

patient a flu shot containing mercury on their way out.

In a 2009 "Neurological Review" Drs Lim, Fox and Lang state: "...it has become

increasingly apparent that the neuropathologic changes of PD extend well beyond

the nigrostriatal system. Even components of the early core motor symptoms may

not be exclusively related to nigrostriatal dopamine deficiency." They go on to say

that "most of the disability brought on by advancing PD relates to the emergence of

symptoms that responds poorly, if at all, to levodopa or modern surgical therapies."

In fact, they say, "Increasing evidence suggests that in most cases the first neurons

affected in PD are nondopaminergic.153

Taking L-dopa advances the progression of Parkinson's at a much faster pace than

not taking L-dopa . This has lead researchers to believe L-dopa is the problem. Of

course some L-dopa becomes dopamine and seems to alleviate symptoms, but the

rest oxidizes, and this is because the underlying disease process (damaged

mitochondria) is still raging.

The Parkinson's Brain Is Toxic To Dopamine

153 Shen-Yang Lim, et al Overview of the Extranigral Aspects of Parkinson's Disease Arch Neurol Vol. 66

(No.2) Feb 2009 Pg 167-172.

"...a thorough understanding of the role of anti-Parkinson medications, such as L-dopa,

dopamine (DA) agonists, catechol-O-methyltransferase (COMT) inhibitors, and

monoamine oxidase (MAO) inhibitors, is needed. As health care providers become more

proficient in the use of these drugs, the prevalence of late complications, or highly

advanced PD, is increasing. Before the development of L-dopa, 30% of patients were

described as having severe disease, but with the genesis of successful anti-PD therapies,

severe disability if reported in 53% of Parkinson's patients 4 years after the diagnosis."

[Mark Stacy, MD. Managing Late Complications of Parkinson's Disease. Parkinson's

Disease And Parkinsonian Syndromes. Vol. 83, No. 2. March 1999.]

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Prior to 1960 doctors didn't even know that Parkinson's had anything to do with

dopamine. It was Ehringer and Hornykiewicz who described Parkinson's disease as

a "dopamine deficiency" disease154

, and patients were given the first dose of

Levodopa (L-dopa) in 1961.155

While drugs to increase dopamine production or

block its oxidation are also often prescribed, L-dopa is the drug against which all

other drugs are compared, said to be the most effective dopaminergic treatment for

Parkinson's aka The Gold Standard.

But why L-dopa? Why not give dopamine? L-dopa can cross the blood brain

barrier, and once in the brain is converted into dopamine. Conversely, dopamine

doesn't cross the blood-brain barrier, and if given as a drug would build up and be

toxic to the rest of the body. In fact, Carbidopa is now routinely combined with L-

dopa. Carbidopa is a drug that restricts L-dopa's conversion to dopamine outside

of the brain (to prevent peripheral toxicity). Carbidopa inhibits an enzyme

(aromatic-L-amino acid decarboxylase) which is important in the conversion of

L-dopa to dopamine, thus preventing L-dopa from becoming Dopamine prior to

reaching the brain. Since Carbidopa cannot cross the blood-brain barrier, once L-

dopa crosses, it can form dopamine unrestrained.

Over the years L-dopa has been shown to have many drawbacks. The side-effect

of nausea and vomiting, caused by L-dopamine's conversion to Dopamine

peripherally, is generally offset by use of Carbidopa. But this leaves the two most

disconcerting side-effects of L-dopa use, which are motor complications that

worsen year after year, and what is seen by researcher's as L-dopa's "potential to

induce free radical-mediated damage and thereby induce and or accelerate nigral

neuronal cell dysfunction and death."156

I'd like to explore that statement, because

with what we now know about mitochondrial damage, we should be able to put

past observations into current perspective.

154 H. Ehringer, O. Hornykiewicz. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the

human brain and their behaviour in diseases of the extrapyramidal system. Klin Wochenschr (1960)

38:1236-1239. 155 W Birkmayer, O. Hornykiewicz. The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia.

Wien Klin Wochenschr (1961) 73:787-788. 156 CW Olanow et al. Levodopa in the treatment of Parkinson's disease: current controversies. Mov

Disord (2004) 19:997-1005.

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Much about dopamine toxicity was observed 40 or more years ago, and has not yet

been "unlearned" by most who read those studies. I think we can show now that

what we have blamed dopamine for doing all these years is not being done by

dopamine, but to dopamine, by the reactive oxygen species generated from

damaged mitochondria.

Consider the next paragraph. Many of these observations are from studies done in

the 1970's and 80's. Most are done in a lab (in vitro) not in humans or even

"primates" (in vivo). These studies note that all of their observations are "poorly

understood, inconclusive, that mechanisms have not been elucidated, and results

are confounded by the in vitro environment being nothing like the in vivo

environment". These and more "disclaimers" continue even as recently as 2009.157

As you consider the next paragraph, note that if you insert that reactive oxygen

species is being generated by damaged mitochondria as that which is actually

oxidizing dopamine, causing it to become a part of the problem instead of the

solution, much of the mystery is solved.

Dopamine undergoes autoxidation, semiquinone formation and polymerization

with the production of radical species.158,159

Dopamine can be metabolized by

monoamine oxidase to produce hydrogen peroxide (H2O2)160

The H2O2 produced

by dopamine, in the presence of iron (Fenton reaction) produces the highly reactive

hydroxyl radical. Yet, you can find these in scientific literature as being

associated with mitochondria as well.

Non-physiological release of synaptic dopamine (such as when excitatory

glutamate causes the release of dopamine161,162

) is thought to play a major role in

157 Arnar Astradsson et al. The Blood-brain barrier is intact after levodopa-induced dyskinesias in

parkinsonian primates-Evidence from in vivo neuroimaging studies. Neurobiology of Disease 35 (2009)

348-351. 158 PG Jenner, DG Graham. Oxidative pathways for catecholamines in the genesis of neuromelanin and

cytotoxic quinones. Mol Pharmacol (1978) 14:633-643. 159 DC Tse et al. Potential oxidative pathways of brain catecholamines J Med Chem (1976) 19:37-40. 160 RN Adams et al. 6-Hydroxydopamine, a new oxidation mechanism. Eur J Pharmacol (1972) 17:287-

292. 161 H. Mount et al. Glutamate Stimulation of 3H Dopamine Release from Dissociated Cell Cultures of Rat

Ventral Mesencephalon. Journal of Neurochemistry Vol 52 (April 1989) Issue 4. 1300-1310.

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dyskinesia (diminishing ability to voluntarily move muscles, and an increasing

presence of involuntary movements like tics and tremors).163

Researchers once

suggested that the dyskinesia might have to do with a disrupted blood-brain

barrier.164

But Astradsson et al found the blood-brain barrier in parkinsonian

primates exhibiting L-dopa-induced dyskinesia to be intact.165

In 2009 researchers found that calcium homeostasis is dysregulated in Parkinson's

patients with "L-Dopa-induced dyskinesias". They found a depressed Ca2+

rise in

response to mitogen-induced activation (which means a chemical substance

encourages a cell to begin cell division). This defect was more pronounced in L-

Dopa-induced dyskinesia patients. They conclude that "second messenger levels

(like cAMP and free intracellular Ca2+) are altered in the peripheral blood

lymphocytes of Parkinson's patients treated with dopaminergic agents", and this

results in further alterations in Ca2+

homeostasis. 166

Along with dopamine toxicity, researchers say they have observed mitochondrial

dysfunction, specifically complex I deficiency.167

Here's a case of the cart pulling

the horse.

On the one hand, research shows that L-dopa can act as a pro-oxidant at high

levels, while conversely, at more normal levels, acts as an antioxidant, inducing the

upregulation of glutathione and other neuroprotective molecules possibly because

162 N.V. Kulagina et al. Glutamate regulates the spontaneous and evoked release of dopamine in the rat

striatum. Neuroscience Vol 102 Issue 1 (January 2001) 121-128. 163 JA Obeso et al. Pathophysiology of levodopa-induced dyskinesias. Ann Neurol 47. (2000) S22-S32. 164 JE Westin et al. Endothelial proliferation and increased blood-brain barrier permeability in the basal

ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia. J Neurosci 26 (2006) 9448-

9461. 165 Arnar Astradsson et al. The blood-brain barrier is intact after levodopa-induced dyskinesias in

parkinsonian primates-Evidence from in vivo neuroimaging studies. Neurobiology of Disease 34 (2009)

348-351. 166 Fabio Blandini MD et al. Calcium HOmeostasis is Dysregulated in Parkinsonian Patients with L-Dopa-

induced Dyskinesias. Clinical Neuropharmacology (May/June 2009) Vol 32, No 3. 133-139. 167 AH Schapira et al. Mitochondrial complex I deficiency in Parkinson's disease. Lancet (1989) 1:1269.

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the drug acts as a "minimal stressor", enhancing the production of these protective

molecules.168,169

Perhaps most importantly is that more recent researchers have cautioned against

placing much relevance upon observations of L-dopa toxicity in vitro culture

because the culture is missing the high ascorbate found in tissues. Thus much of

the in vitro evidence for a toxic effect by dopamine on neuronal cells may very

well be "artifactual" and not the same as would be observed within the body.170

In

addition, many studies that have demonstrated L-dopa toxicity in culture, used

rather high concentrations of L-dopa, that is, >50μM/L compared to the typical 10-

20 μM/L given to patients, of which only about 12% actually shows up in the

cerebrospinal fluid.171

Scientists have noted that when glial cells (the brain's "immune system") and

ascorbate have been added to cultures testing for L-dopa toxicity, because this

becomes a scenario more like that found in the substantia nigra, L-dopa toxicity

was significantly diminished or even abolished altogether!172,173

It seems extreme measures have to be taken to induce L-dopa toxicity in rats. High

levels of L-dopa were injected into them in the presence of iron to cause toxicity.174

168 C Mytilineou et al. Toxic and protective effects of Levodopa on mesencephalic cell cultures. J

Neurochem (1993) 61:1470-1478. 169 MA Mena et al. Neurotrophic effects of L-dopa in postnatal midbrain dopamine neuron/cortical

astrocyte cocultures. J Neurochem (1997) 69:1398-1408. 170 MV Clement et al. The cytotoxicity of dopamine may be an artefact of cell culture. J Neurochem

(2002) 81:414-421. 171 CW Olanow et al. Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics

of levodopa and clinical effect in Parkinson's disease. Ann Neurol (1991) 29:556-559. 172 MA Mena et al. Glia protect fetal midbrain dopamine neurons in culture from L-dopa toxicity through

multiple mechanisms. J Neural Transm (1997) 104:317-328. 173 C. Mytilineou et al. Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of

oxidative stress. J Pham Exp Ther (2003) 304:792-800. 174 H Maharaj et al. Levodopa administration enhances 6-hydroxydopamine generation. Brain Res (2005)

1063:180-186.

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On the other hand, in normal rodents and primates, administration of large

quantities of L-dopa caused no toxicity.175,176

It's what Dr. Schapira says after the quote above that returns us nicely to the

mitochondria: "Finally, clinical studies have failed to support the concept of L-

dopa toxicity, but imaging studies do not permit this concept to be completely

excluded." Indeed! Because what we are seeing is dopamine being oxidized by

reactive oxygen species generated from damaged mitochondria, not some

mysterious "auto" oxidation of dopamine.

That said, of course we do need to understand that the bottom line in Parkinson's

with regard to dopamine toxicity, is that dopamine is being oxidized, but it is

because of the brain's environment. This is important because until a Parkinson's

patient can obtain therapies that completely replace/repair damaged mitochondria,

measures must be applied to quell the vicious cycle of oxidative damage to

dopamine, and resultant oxidative damage then done by oxidized dopamine.

Some of the things going on we've discussed already, consider any repeat to be a

refresher. This section is to show how the underlying damage to the mitochondria

is the cause of "all the other things going on". In the final analysis, stopping

ongoing damage to mitochondria and applying therapies targeted at healing the

mitochondria is the only way we are ever going to heal Parkinson's.

Mitochondrial Membrane, Electron Transfer Chain Dysfunction

175 F. Hefti et al. Long term administration of Levodopa does not damage dopaminergic neurons in the

mouse. Neurology (1981) 31:1194-1195. 176 TL Perry et al. Nigrostriatal Dopaminergic neurons remain undamaged in rats given high doses of

Levodopa and carbidopa chronically. J Neurochem (1984) 43:990-993.

Animal models have not provided evidence that L-dopa is toxic in animals that are

normal, dopamine-lesioned, or subject to oxidative stress. In fact there is even a

suggestion that L-dopa has the potential to protect nigrostriatal neurons through a variety

of mechanisms that include growth factor induction. [Anthony H.V. Schapira M.D., DSc,

FRCP, FMedSci. The Clinical Relevance of Levodopa Toxicity in the Treatment of

Parkinson's Disease. Movement Disorders Vol 23, Suppl 3 (2008) S515-S520.

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"Complex I" is NADH dehydrogenase (also referred to as NADH: quinone

reductase) is an enzyme located in the inner mitochondrial membrane. NADH is

used to catalyze the transfer of electrons from NADH to Coenzyme Q. Complex I

produces superoxide as well as hydrogen peroxide. Both of these free radicals are

seen in excess in Parkinson's. Complex I is the "entry enzyme" of oxidative

phosphorylation in the mitochondria. Phosphorylation is the addition of a

phosphate group (PO4) to protein enzymes to activate them (via enzymes called

kinases) or deactivate them (via enzymes called phosphatases).

Calcium Homeostasis

Calcium Homeostasis is the term for when the body is maintaining adequate

calcium levels. But it is also used to denote a proper balance of calcium within

cells and outside of cells. A proper balance of calcium flowing into and out of

cells would indicate homeostasis of calcium. Excess calcium flowing into cells

would be called in influx, and excess calcium flowing out of cells would be called

an efflux.

Ca2+ (calcium ion) efflux is seen in Parkinson's. Many substances were tested on

heart mitochondria to see which increased Ca2+ efflux the most. Of all the

substances tested, methyl mercuric chloride was the most effective since it was

active at ratios of about 1 nmol/mg of mitochondrial protein.177

Acetylcholine receptors found in the plasma membrane of certain neurons as well

as other cells (muscarinic ACh receptors) when incubated with mercury in vitro

caused calcium release from intracellular stores.178

Mercury-induced damage has been observed to organelles which store calcium

(e.g., the smooth endoplasmic reticulum and the mitochondrion) which led to

increased intracellular calcium levels.179

177 EJ Harris and H Baum. Production of thiol groups and retention of calcium ions by cardiac

mitochondria. Biochem J. 1980 March 15;186(3):725-732. 178 TL Limke et al. Disruption of intraneuronal divalent cation regulation by methylmercury: are specific

targets involved in altered neuronal development and cytotoxicity in methylmercury poisoning?

Neurotoxicology (2004) 25 741-760.

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Mercury inhibits sarcoplasmic ATPases (a class of enzymes that catalyze the

decomposition of adenosine triphosphate) resulting in an altered calcium

homeostasis.180

The sarcoplasm is the cytoplasm (the part of a cell that is enclosed

within the cell membrane) of a muscle fiber and has a high concentration of

calcium used for muscle contractions.

In excitable cells like neurons, the mitochondrial membrane contains a protein

(NCX) that removes calcium from cells (one ion in exchange for 3 ions of sodium).

Recent studies suggest that "supraphysiological activation" of NCX contributes to

neuronal cell death and reduces the ability to reestablish normal ionic

homeostasis.181

Supraphysiological activation just means that something out of

the ordinary has occurred outside of normal physiological body functioning to

cause activation of NCX. Of course toxins, and mercury is the primary suspect,

would be just that, out of the ordinary.

Researchers in 1997 found a Parkinson's disease link to defects in mitochondrial

function. When they bypassed complex I with succinate, they were able to

partially restore suppressed recovery rates of cytosolic calcium increase. They

concluded that the "subtle alteration in calcium homeostasis of Parkinson's disease

cybrids (mitochondrially transformed cells) may reflect an increased susceptibility

to cell death under circumstances not ordinarily toxic."182

How Does Increased Intracellular Calcium Lead To Toxicity?

It is known that the removal of extracellular calcium increases survival rate of

neurons in vitro.183

Elevated calcium levels lead to cell death either by apoptotic or

necrotic pathways. Calcium activates the protease calpain (a protein belonging to

the family of calcium-dependent, non-lysosomal cysteine proteases). When

179 AP Somlyo et al. Calcium content of mitochondria and endoplasmic reticulum in liver frozen rapidly in vivo. Nature (1985) 314, 622-625. 180 JJ Abramson et al. Heavy metals induce rapid calcium release from sarcoplasmic reticulum vesicles isolated from skeletal muscle. Proc Natl Acad Sci U.S.A, (1983) 80 1526-1530. 181 P. Castaldo et al. Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in

the pathogenesis of neurological diseases. Progress in Neurobiology 87 (2009) 58-79. Italy. 182 JP Sheehan et al. Altered Calcium Homeostasis in Cells Transformed by Mitochondria from Individuals

with Parkinson's Disease. Journal of Neurochemistry (March 1997) Vol 68, No 3. 1221-1233. 183 DW Choi. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett (1985)

58, 293-297.

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calpain is abnormally activated, it leads to cleavage of vital proteins which results

in damage to and death of cytoskeleton (cellular "scaffolding" or "skeleton" made

of protein contained within the cytoplasm [interior of cells]).184

Calcium-activation of phospholipase A2 (an enzyme involved in fatty acid

metabolism in cell membranes) disrupts membrane stability which ultimately leads

to death of the cell.185

In normal brains cells, phospholipase A2 regulates the

balance between inflammatory and antiinflammatory fatty acids in cell

membranes. Increased phospholipase A2 is associated with many inflammatory

conditions, including neurological diseases.

N-methyl-D-aspartic acid (NMDA) is an amino acid derivative which acts as a

specific agonist at the NMDA receptor mimicking the action of glutamate. NMDA

receptors are a type of glutamate receptor where upregulation has been seen in

neuronal injury. Researchers in 2005 discuss how in previous studies, NMDA

antagonists failed to treat stroke/neurotrauma patients. Newer studies indicate it

would have been because the time period in which initial NMDA receptor up-

regulation occurs is critical. Only when NMDA antagonists are employed during

extracellular calcium reperfusion neurotoxicity can be abated.186

Genes, Genetic Mutations, Protein Mutations

The so-called "familial Parkinson's" because of pathogenic mutations in genes such

as a-synuclein, parkin, DJ-1, PINK1, LRRK2, and HtrA1 has been shown to

either directly or indirectly link their pathogenic roles with mitochondrial

dysfunction.187,188

Mice with increased mitochondrial accumulation of human a-

synuclein developed significant mtDNA damage and impaired cytochrome oxidase

184 KK Wang. Calpain and caspase: can you tell the difference? Trends Neurosci (2000) 23, 20-26. 185 UA Boelsterli. Mechanistic Toxicology: The molecular basis of how chemicals disrupt biological targets. New York: Taylor & Francis. (2003) 186 Xin Wen-Kuan et al. The removal of extracellular calcium: a novel mechanism underlying the

recruitment of N-methyl-D-aspartate (NMDA) receptors in neurotoxicity. European Journal of

Neuroscience (February 2005) Vol 21, No 3. 622-636. 187 Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet 2007;16 (Spec No. 2): R183-R194. 188 Konstanze F et al. Mitonchondrial dysfunction in Parkinson's disease. Biochimica et Biophysica Acta

1802 (2010) 29-44.

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(Complex IV) activity which led to mitochondrial dysfunction. The researchers

reported that the mitochondrial dysfunction led to increased susceptibility to

neurodegeneration induced by mitochondrial toxins.27

Indeed, many studies have

now shown a direct link between parkin and its role in mitochondrial function,

especially its ability to interact with mitochondrial transcription factor A (Tfam)

to enhance mitochondrial biogenesis.189

Studies with mice and a conditional

knockout of transcription factor A caused progressive loss of nigrostriatal

dopaminergic neurons as seen in Parkinson's.190

Because mercury is a widespread contaminant, researchers deliberately fed

zebrafish a mercury-contaminated diet for 25 days to see the effects on gene

expression.

It is also interesting to note that researchers have identified a "subset" of

individuals who they say are exceptionally vulnerable to the toxic effects of

mercury. As I go on to explain why, also consider that it has been shown that

people who get flu shots (with mercury) year after year are many-fold more likely

to get Alzheimer's later in life than those who do not get flu shots.

That said, people who have been identified with the genotype APOe 4/4 are

considered at risk for developing Alzheimer's. The APOe 4/4 gene has two binding

sites that contain arginine, whose job it is to remove excess cholesterol from the

brain. There is also an APOe 2/2 gene, not prevalent in the brains of those who are

genotype APOe 4/4. APOe 2/2 gene makes a transport vehicle that has four

binding sites that contain sulfur. The sulfur, as we've discussed, has an

extraordinary affinity for mercury, and is thus protective, as a vehicle to transport

mercury out of the brain. The arginine in the APOe 4/4 gene does a wonderful job

of transporting cholesterol, but it has no affinity for mercury. APOe 2/2 gene is

protective against AD and APOe 4/4 is predictive of early onset. Of course, if

mercury weren't being ingested, it is likely that even the APOe 4/4 individual

would not succumb to Alzheimer's or any other neurological disease. And so it is,

189 Kuroda Y et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet

2006;15:883-895. 190 Ekstrand MI et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine

neurons. Proc Natl Acad Sci USA 2007;104:1325-1330.

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that mercury levels are found to be 4-fold higher in the Alzheimer's brain vs. a

"normally aged" brain.191,192

Perturbed Endoplasmic Reticulum Function

Note in the study below, that mercury perturbed endoplasmic reticulum

function. Proper endoplasmic reticulum function is responsible for the folding and

processing of newly synthesized proteins, calcium storage and cell signaling. A

malfunction of each of these is seen in neurological diseases.193

Immune System Disruption

There are also many studies seeking to discern how the immune system might be

linked to Parkinson's. Researchers have found that exposure to mercury, acting

through membrane proteins, disrupts integrin signalling/functional pathways in

191 WR Markesbery et al. Brain Trace Element Concentrations in Aging Neurobiology of Aging.

Neurobiology of Aging (1984) Vol 5. 19-28. 192 WD Ehman et al. Application of Neutron Activation analysis to the Study of Age Related Neurological

Diseases. Biol Trace Elem Res (1987) Vol 5. 19-33. 193 Shastry BS. Neurodegenerative disorders of protein aggregation. Neurochem Int 2003;43:1-7.

A net impact of methylmercury was noticed on 14 ribosomal protein genes, indicating a

perturbation of protein synthesis. Several genes involved in mitochondrial metabolism,

the electron transport chain, endoplasmic reticulum function, detoxification, and general

stress responses were differentially regulated, suggesting an onset of oxidative stress and

endoplasmic reticulum stress. Several other genes for which expression varied with

methylmercury contamination could be clustered in various compartments of the cell's

life, such as lipid metabolism, calcium homeostasis, iron metabolism, muscle

contraction, and cell cycle regulation. [Cambier S et al. Serial analysis of gene expression

in the skeletal muscles of zebrafish fed with a methylmercury-contaminated diet. Environ

Sci Technol. 2010 Jan 1;44(1):469-475.]

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neutrophils.194

Integrins are receptors that mediate attachment between a cell and

the tissues surrounding it.

The inflammatory response is part of a healthy immune system, acting to

counteract infections and injury. It is only when inflammation is excessive or

chronic that we see neurodegeneration. The microglia are associated with

inflammation. Microglia are the "resident macrophages" of the brain and spinal

cord. Microglia constantly scavenge the central nervous system cleaning up

plaques, infectious agents and damaged or dead neurons. To induce Parkinson's in

lab animals, scientists inject the animal with substances that activate microglia.

Some of these substances are rotenone, paraquat, 6-hydroxydopamine (6-OHDA)

and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Because microglia

initiate the inflammatory response, if the activation of microglia is continuous, the

inflammation will be excessive or chronic (as happens when toxic damage has

occurred) and dopaminergic neurons will be damaged or killed as seen in

Parkinson's.195

Neurons Firing Wildly Out of Control

It's been shown that restless leg syndrome is from a "neurological firestorm"

which refers to neurons firing wildly out of control. Migraines are also the result of

a neurological firestorm. Likely all aberrant movement and pain within

neurological diseases can be labeled as a result of a neurological firestorm. This is

critical to bring to the forefront, because involved in neurological firestorms are

excessive glutamate and nitric oxide release. Neurons fire wildly out of control

because of excessive glutamate release at the synapse, and then nitric oxide's

excessive creation and/or attempt to come to the rescue. Which leads us to the

reason most/all Parkinson's patients should likely not be given glutathione. As we

have seen, damage to mitochondria, glutathione and glutamate dehydrogenase in

the bodies of people with Parkinson's and other neurological diseases, prevents the

proper use of glutathione, and so it breaks down and releases free glutamates.

Glutathione Deficiency

194 RG Worth et al. Mercury inhibition of neutrophil activity: evidence of aberrant cellular signalling and

incoherent cellular metabolism. Scand J Immunol (2001 Jan) 53(1):49-55. 195 PS Whitton. Inflammation as a causative factor in the aetiology of Parkinson's disease. Br J Pharmacol

(2007) 150:963-976.

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The main reason there is that deficiency of glutathione is discussed in this study:

"Mercury can accumulate in mitochondria because of their high affinity for binding

thiols (sulfur-containing molecules), leading to the depletion of mitochondrial

glutathione."196

Apparently giving oral glutathione is not the best method of boosting glutathione

levels anyway. In a study by Reddy et al called The systemic availability of oral

glutathione, he states: When seven healthy people were given a single application

of up to 3,000 mg of glutathione, there was no increase in blood glutathione levels.

The human gastrointestinal tract contains significant amounts of an enzyme

(gamma-glutamyltranspeptidase) that breaks down glutathione.197

I reiterate that

glutathione, broken down, generates "free glutamates" which have been implicated

in numerous diseases as a damaging factor, including Parkinson's.

One way to increase glutathione safely is stated in this study: "...in one trial, blood

glutathione levels rose nearly 50% in healthy people taking 500 mg. of vitamin C

per day for only two weeks."198

Another way is to consume copious quantities of

sulfur-containing food.199

Up-Regulation of Gamma-Glutamyltranspeptidase

Homocysteine

One extremely significant adverse effect observed along with L-dopa therapy (and

again, most likely due to mitochondrial production of free radicals, including

oxidized dopamine) is the increase in total homocysteine in the blood which has

been linked to affective/cognitive impairment, dyskinesia and vascular disease in

patients with Parkinson's.200,201,202,203

196 Charles R Arthur et al Parkinson's Disease Brain Mitochondria Have Impaired Respirasome Assembly,

Age-Related Increases in Distribution of Oxidative Damage to mtDNA and No Differences in

Heteroplasmic mtDNA Mutation Abundance. Molecular Neurodegeneration 2009 4:37. 197 Witschi A. Reddy et al. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992.

43:667-9. 198 Am J Clin Nutr 1993;58:103-5. 199 Sulfur amino acid deficiency depresses brain glutathione concentration. Nutr Neurosci 2001;4(3):213-

22. 200 P.E. O'Suilleabhain et al. Elevated plasma homocysteine level in patients with Parkinson disease:

motor, affective and cognitive associations. Arch Neurol (2004) 61:865-868.

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Homocysteine is a sulphur-containing amino acid formed by the demethylation of

the amino acid methionine. Research has shown that homocysteine normally is

"recycled" by enzymes in the body, which break it down into component parts

methionine and cysteine. This process requires folate (comes from the word

"foliage", and is abundant in raw fruits and vegetables) and vitamin B12. This

vitamin is most commonly obtained from animal-source proteins or is best

supplemented in the form of methylcobalamin sublingual or injections.

Glutathione, N-acetylcysteine and GGT

We discussed earlier how sulfhydryl groups (also called thiols) are damaged by

mercury, peroxynitrite and other reactive oxygen species. The thiol-containing

glutathione (GSH) and N-acetylcysteine (NAC) are powerful antioxidants within

a healthy body. In Parkinson's these crucial antioxidants are known to be grossly

depleted (as they would be by mercury, a poor diet, other toxins and mitochondrial

damage continuously spewing out free radicals). These two antioxidants have

shown powerful inhibition of dopamine toxicity in lab tests.204

201 JD Rogers et al. Elevated plasma homocysteine levels in patients treated with levodopa: association

with vascular disease. Arch Neurol (2003) 60:59-64. 202 S Zoccolella et al. Elevated plasma homocysteine levels in L-dopa-treated Parkinson's disease patients

with dyskinesias. Clin Chem Lab Med (2006) 44:863-866. 203 Martin-Fernandez JJ et al. Homocysteine and cognitive impairment in Parkinson's disease. Rev Neurol

(Feb 1-15, 2010) 50(3):145-151. 204 Daniel Offen et al. Prevention of Dopamine-Induced Cell Death by Thiol Antioxidants: Possible

Implications for Treatment of Parkinson's Disease. Experimental Neurology 141, (1995) 32-39.

Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of L-Dopa, the main pharmacological treatment of PD. [E. Martignoni et al. Homocysteine and Parkinson's disease: A dangerous liaison? Journal of the Neurological Sciences (2007) Vol 257 Issue 1 31-37.

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But the human body isn't a Petri dish or lab animal. First you need to know that

glutathione is made up of the amino acids L-cysteine, L-glutamate and glycine.

The liver & lungs are where most glutathione is made. Glycine & glutamic acid are

plentiful within the body, so it is the availability of cysteine that controls how

much glutathione you can make.

When human subjects were given 3,000 mg of glutathione there was no increase in

blood glutathione levels because the human gastrointestinal tracts contacts

gamma-glutamyltranspeptidase (GGT) which breaks down glutathione.205

This

generates free glutamates, which is toxic, and already elevated in Parkinson's. But

GGT is also found up-regulated in the substantia nigra of Parkinson's (who have

depleted glutathione) thought to be a "sparing" act of the brain, in response to

depleted glutathione.206

Giving intravenous glutathione could therefore be contrary

to good medical practice for Parkinson's, because the GGT would break it down in

the brain causing excess free glutamates and further excitotoxic activity.

So what about supplementing NAC? It would seem to be the miracle everyone

depleted of glutathione would need. Unfortunately, taking it as a supplement is a

double-edged sword in people with mitochondrial damage. When the brain

contains (as it does in Parkinson's) high levels of homocysteine, add more cysteine,

and you actually cause oxidative stress in the presence of iron and copper (redox-

active transition metal ions).207,208,209

In addition, taking NAC, which would result

in an increase in glutathione, would only be broken down by GGT in the Parkinson

brain, generating excess glutamate. Excess glutamate, in addition to causing

excitotoxic neuronal death, causes excess nitric oxide, a potent vasodilator which

leads to inflammation and headaches.

205 A Witschi et al. The systemic availability of oral glutathione. Eur J Clin Pharmacol (1992) 43:667-669. 206 SJ Chinta et al. Up-regulation of gamma-glutamyltranspeptidase activity following glutathione

depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity:

implications for Parkinson's disease. Free Radic Biol Med (2006) 40(9):1557-1563. 207 YZ Tang et al. Free radicals, antioxidants and nutrition. Nutrition (2002) 18:872-879. 208 RA Patterson et al. Mechanisms by which cysteine can inhibit or promote the oxidation of low density

lipoprotein by copper. Atherosclerosis (2003) 169:87-94. 209 P Munoz et al. Differences between cysteine and homocysteine in the induction of deoxyribose

degradation and DNA damages. Free Radic Biol Med (2001) 30:352-362.

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Giving intravenous glutathione is actually a common practice and seems to help

some patients. In others there is no response or they get worse. However, since

no-one is cured by intravenous glutathione, it appears that it may be like beating a

dying horse. He runs a little longer, and a little harder, but then eventually dies

because the underlying problems have not been addressed. The safest way to

increase glutathione is not by beating the horse, but by gently nurturing it back to

life.

So what's the answer for Parkinson's sufferers? Instead of trying to elevate

glutathione by taking NAC or glutathione, the Parkinson's patient should maintain

a diet devoid of dietary free glutamates, and high in sulfur (cysteine is a sulfur-

containing amino acid) and vitamin C. These two nutrients have been shown to

increase glutathione dramatically.210,211

The Need For Ascorbic Acid

In a 1975 study researchers tell of a 62-year old man who had done well on large

doses of levodopa initially, and then intolerable side-effects caused him to

terminate treatment. He was later restarted on a reduced level (3g) of levodopa

along with ascorbic acid, 1 gram per day, and gradually increased to 4 grams,

while at the same time, the L-dopa was reduced (2g) per day. It was reported that

the patient "almost immediately" reported a decrease in side-effects. He was, in

fact, able to return to doing the things he loved. To test that it was, indeed, the

ascorbic acid causing the beneficial effects, the researchers put him on placebo and

found that within two weeks the benefits disappeared. 212

So how much vitamin C do we need? Dr. Irwin Stone produced a table showing

how most mammals (except bats, humans, monkeys and guinea pigs) produce the

ascorbic acid they need in their liver. On his table, it shows that a goat, which

210 CS Johnston et al. Vitamin C elevates red blood cell glutathione in healthy adults. American Journal of

Clinical Nutrition Vol 58 (1993) 103-105. 211 PG Paterson et al. Sulfur amino acid deficiency depresses brain glutathione concentration. Nutr

Neurosci (2001) 4(3):213-222. 212 William Sacks, George M. Simpson. Ascorbic Acid in Levodopa Therapy. The Lancet. March 1, 1975. P.

527

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would be about the size of a man, produces up to about 13 grams of vitamin C

daily.213

Because of this, "Dr. Vitamin C", Dr. Linus Pauling recommended

between two and ten grams of vitamin C daily for people, at a time when most

vitamin manufacturers were wary of producing supplemental vitamin C higher

than about 100 mg. Mammals that do not produce their own vitamin C have lost

one of the four enzymes (L-gulonolactone oxidase) that converts blood glucose

into ascorbate in the liver.214

Ascorbic acid has been shown to appreciably reduce the effect of MPTP

neurotoxicity.215

Protein cross-linking seen in neurological diseases, was

diminished in the presence of ascorbate.216

It is known that ascorbic acid can behave as an antioxidant, but also as a pro-

oxidant. The pro-oxidant ascorbic acid adds electrons to transition metals like

copper and iron, which can generate superoxide and other reactive oxygen species.

One study shows that intravenous use of vitamin C does not seem to increase pro-

oxidant activity217

however in Parkinson's patients the known elevation of iron may

make intravenous vitamin C use unwise.

Are Drugs an Insult to Injury?

Long-term L-dopa therapy is known to lead to major complications. By now I

think we can see that the evidence shows that dopamine isn't causing the toxicity,

but that toxicity is causing dopamine to oxidize. Without coming to that

conclusion, however, researchers are searching for drug alternatives. One

possibility is adenosine A2A receptor antagonists (A2A). A2A receptors in the

213 I. Stone. New Dynamics of Preventive Medicine. 1974 2:19. 214 I. Stone. "Eight Decades of Scurvy. The Case History of a Misleading Dietary Hypothesis". July 16,

1978. 215 H. Sershen et al. Protection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Neurotoxicity By

The Antioxidant Ascorbic Acid. Neuropharmacology (1985) Vol 24. No. 12. 1257-1259. 216 Jennifer N. Rees et al. Protein Reactivity of 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine

Metabolite, Is Dependent on Both the Aldehyde and the Catechol. Chem Res Toxicol (2009) 22:1256-

1263. 217 A. Mühlhöfer et al. High dose intravenous vitamin C is not associated with an increase of pro-

oxidative biomarkers. European Journal of Clinical Nutrition (2004). 58(8):1151-1158.

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brain play important roles in the regulation of glutamate and dopamine release.

A2A receptors are especially concentrated in brain areas naturally rich in dopamine.

In pharmacology, when a receptor is upregulated within a disease, the attempt is to

apply an antagonist as a therapeutic intervention. The problem is that the

antagonist works in some cases, but not others, and worse, often causes serious,

even life-threatening side-effects.

Is there a better way than A2A antagonists? In the cascade of events stemming

from mitochondrial damage, we see elevated levels of glutamate. As we've seen,

glutamate is a neurotransmitter, which in excess is an excitotoxin, leading to

neuronal death. Since studies have shown that A2A antagonists sometimes

improves motor symptoms in Parkinson's,218

it could very well be that it works by

reducing the excitotoxic effects of glutamate. This is an important consideration,

because glutamate excess is only one of many things going on in Parkinson's. The

better approach to controlling all of the things going on is not a drug that only

partially works, and could be dangerous, but to stop "all the things going on" in the

first place. Prevention and repair of the underlying mitochondrial damage again

emerges as where our efforts should lie.

To this day much confusion exists. Study after study will outline the pathological

changes and motor dysfunctions seen in Parkinson's; that oxidative stress is

involved; that there are alterations in endogenous antioxidant systems like SOD

and glutathione; that iron is present in excess; that lipids and proteins are oxidized;

and that in the end, dopamine becomes toxic219

causing dopaminergic neurons to

be killed. Researchers will examine each of these and wonder which of these

events came first, and which is the "cause" of Parkinson's. One study says that the

"current major hypothesis is that nigral neuronal death in PD is due to excessive

oxidative stress generated by auto and enzymatic oxidation of the endogenous

neurotransmitter dopamine (DA)."220

Isn't this just saying that Parkinson's happens

218 Micaela Morelli et al. Role of adenosine A2A receptors in parkinsonian motor impairment and L-DOPA-

induced motor complications. Progress in Neurobiology. (2007) 83:293-309. 219 Daniel Offen et al. Dopamine-melanin induces apoptosis in PC12 cells; possible implications for the

etiology of Parkinson's disease. Neurochem Int (Aug 3, 1997) 31(2):207-216. 220 Ari Barzilai et al. Is There a Rationale for Neuroprotection Against Dopamine Toxicity in Parkinson's

Disease? Cellular and Molecular Neurobiology. (2001) Vol 21, No 3. 215-235.

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out of nothing, from nowhere? The old, "I was walking along, minding my own

business, and out of nowhere..." When we insert mercury or other known toxin as

causing the initial damage to mitochondria, which then continue to reproduce other

damaged mitochondria, and the damaged mitochondria then produces many toxic

reactive oxygen species, perhaps in the least we can begin to focus our efforts in

the right direction.

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CAN WE REPAIR DAMAGED MITOCHONDRIA?

"Mitochondrial membrane permeabilization" which involves the release of proteins

from the mitochondrial intermembrane space, is commonly regarded as the "point

of no return" in the cascade of events that lead to cell death.221

Unfortunately this

would be why Parkinson's and other neurological diseases involving mitochondrial

damage are not much closer to being cured today than nearly 200 years ago at the

time of James Parkinson's essay. This whole mess, that we now know, begins with

devastating damage to the mitochondria, has proven to be a "hard nut to crack."

But has this been because we've been barking up the wrong tree?

One review discusses the "new role" of mitochondria in regulation of neuronal cell

death of neurodegenerative disorders. They say that there are recent findings on

new functions of mitochondria in regulation of their redox state and function

through reversible S- glutathionylation. They go on to list the mitochondria as

being at the beginning of the "apoptotic cascade", which involves a defect of

complex I detected in the outer membrane of the mitochondria which increases

production of reactive oxygen and nitrogen species in mitochondrial oxidative

phosphorylation system. Oxidative damage to proteins, lipids and DNA occur

along with reduced anti-oxidant activities. The mitochondrial permeability

transition is followed by release of apoptosis-inducing factors (AIFs) such as

cytochrome c in cytoplasm, activation of caspase 9 and 3, and finally

fragmentation and condensation of nuclear DNA. They say that the various genes

in familial Parkinson's (Parkin, PINK1, DJ-1, LRRK2, PARK8) directly or

indirectly regulate mitochondrial function and integrity.222

Does mercury "mutate"

the genes necessary for optimal functioning of the mitochondria in Parkinson's and

other "mitochondrial" diseases?

Consider Blackinton et al, 2008, where they discuss DJ-1, a protein associated with

"inherited Parkinsonism". DJ-1 is normally protective of mitochondrial function in

Parkinson's. The researchers discuss how DJ-1 readily forms cysteine-sulfinic acid

complex. They say that "Mutation of cysteine causes the protein to lose its normal

protective function in cell culture and model organisms." They go on to say, in

effect, that they haven't got a clue why the protein loses its protective function.

They conclude that the formation of cysteine-sulfinic acid is a key modification

221 Vladimir Gogvadze et al. Mitochondria as targets for chemotherapy. Apoptosis (2009) 14:624-640. 222 Makoto Naoi et al. Mitochondria in neurodegenerative disorders: regulation of the redox state and

death signaling leading to neuronal death and survival. J Neural Transm September 18, 2009.

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that regulates the protective function of DJ-1. I propose that if we insert mercury

into the equation as that which "mutates" the cysteine (molecular structure:

C3H7NO2S, where "S" is sulfur not to mention the "sulfinic acid" it bonds with), we

likely supply the missing puzzle piece.223

Thankfully the research on mitochondrial dysfunction continues. In 2010, a study

on human placental mitochondria, showed that the combination of melatonin with

ascorbate with alpha-tocopherol nearly completely inhibited lipid peroxidation as

seen in Parkinson's.224

CoQ10 is a potent free radical scavenger in the inner mitochondrial membranes.225

It participates in the production of ATP, and in reducing oxidative stress, thus

blocking cell death.226

CoQ10 inhibits mitochondrial permeability transition pore

known to cause cell death by increased retention of mitochondrial calcium.227

CoQ10 blocks nigrostriatal dopaminergic neurodegeneration in tests using various

neurotoxic agents in various ages of lab mice.228

A combined strategy of using creatine and CoQ10 has shown significant

synergistic neuroprotective effects in laboratory studies.229

Creatine

supplementation will increase already elevated nitric oxide in Parkinson's,

however, and should not be supplemented. Obtaining creatine from a diet

containing high quality protein should probably be the only way to "supplement"

creatine.

223 Jeff Blackinton et al. Formation of a Stabilized Cysteine Sulfinic Acid is Critical for the Mitochondrial

Function of the Parkinsonism Protein DJ-1. The Journal of Biological Chemistry. Vol. 284, No. 10. March

6, 2009. 224 Milczarek R et al. Melatonin enhances antioxidant action of alpha-tocopherol and ascorbate against

NADPH- and iron-dependent lipid peroxidation in human placental mitochondria. 225 Beal MF. Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol 2003;53

(Suppl 3) S39-S47; discussion S47-S48. 226 Alleva R. et al. Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing

mitochondrial antioxidant protection. FEBS Lett 2001;503:46-50. 227 Papucci L et al. Coenzyme Q10 prevents apoptosis by inhibiting mitochondrial depolarization

independently of its free radical scavenging property. J Biol Chem 2003;278:28220-28228. 228 Beal MF et al. Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP)

induced loss of striatal dopamine and dopaminergic axons in aged mice. Brain Res 1998;783:109-114. 229 Yang et al., unpublished results as of 2010, as reported by Bobby Thomas PhD and M. Flint Beal, MD.

81 | P a g e

Some other mitochondrially-targeted therapies include MitoQ, currently being

studied in New Zealand. MitoQ is the mitochondrially-targeted peptide

antioxidant SS-31. It is a derivative of mitochondrial quinoline. It converts H2O2

to H2O and O2 to reduce toxicity from free radicals in the mitochondria. It has

been shown to be effective in many in vivo models of mitochondrial dysfunction.230

Much more on mitochondrially-targeted antioxidants later.

Some potential drug therapies being currently explored are PPAR-gamma

coactivator 1alpha (PGC-1a) and the sirtuin family of enzymes both of which

have been shown effective in mitochondrial biogenesis.231,232

Mitochondrial Transplant

Researchers at Newcastle University took the nucleus from a human embryonic

cell and transplanted it into an anucleated human cell. This "swapped" the

mitochondria, and other organelles in the cytoplasm. In essence, this would be

similar to an organ transplant from another person to save a life. A reporter,

writing about this, asked, "why not?" If someone with muscular dystrophy,

multiple sclerosis, heart or any other "mitochondrial disorder" needed it to save

their life, why wouldn't you do a mitochondrial transplant? Might this be the

answer for Parkinson's?233

Apparently, the U.S. and Australia call this "cloning".

But the Council of Europe's 'Convention on Human Rights with Regard to

Biomedicine' states:

Article 13 - Interventions on the human genome: An intervention seeking to

modify the human genome may only be undertaken for preventive, diagnostic or

therapeutic purposes and only if its aim is not to introduce any modification in the

genome of any descendants.

Well, this applies to Parkinson's patients. Of course with what we know/suspect

about mercury's damage to the mitochondria, every Parkinson's patient has a right

to have a mitochondrial transplant to overcome the devastation caused to their

230 Cocheme HM et al. Mitochondrial targeting of quinones: therapeutic implications. Mitochondrion

2007;7 (suppl):S94-S102. 231 McGill et al. PGC-1a, a new therapeutic target in Huntington's disease? Cell 2006;127:465-468. 232 Nemoto S et al. SIRT1 functionally interacts with the metabolic regulator and transcriptional

coactivator PGC-1(a). J Biol Chem 2005;280:16456-16460. 233 Mitochondrial transplant for human embryos. Thursday, 14 February, 2008.

http://hplusbiopolitics.wordpress.com/2008/02/14/mitochondrial-transplant-for-human-embryos

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body by mercury. Especially since they are damaged, due to no fault of their own,

but to the fault of the government for allowing mercury in industry, dentistry, and

medicine, long past when it's devastating effects have been known and ignored.

In 2010 the University of Newcastle's Mitochondrial Research Group in England

stated that treatment options for "mitochondrial myopathies" are limited, in spite of

our current understanding of the problem! They do, however, state that beneficial

to improving mitochondrial function are exercise training and CoQ10 above all.

They say that there are other strategies, including the "ketogenic diet" that need

more research.234

Of course, if we keep poisoning ourselves with mercury, all the

benefits from any therapy will be for naught.

Stem Cell Therapy

As of 2010 stem cell research continues. Results are encouraging, but not long-

lasting. However, mitochondrial-dysfunction is not yet the primary focus.

One study says: "They suggested two processes that put dopamine neurons at risk:

the function of cellular machinery for degrading proteins and organelles, and

oxidative stress secondary to uptake and sequestration of dopamine."235

With all

we've discussed heretofore, inserting mercury and mitochondrial dysfunction into

these researchers' equation would likely clear up a lot of the mystery.

"Over the past quarter century, many experimental replacement therapies have

been tried on PD animal models as well as human patients, yet none resulted in

satisfactory outcomes... Eventually, nearly all of the dopaminergic neurons die of

degeneration, and patients become unresponsive to L-dopa."236

Even the title of

this study tells the frustrating story: "Cells therapy for Parkinson's disease - so

close and so far away."

And why "so far away", indeed? Without addressing dysfunctional mitochondria

that are spewing out deadly free radicals, and repairing components of

mitochondrial respiration that are not functioning properly, and somehow replacing

normally protective endogenous antioxidants that are damaged, no amount of stem

234 Hassani A et al. Mitochondrial myopathies: developments in treatment. Curr Opin Neurol 2010 Jul 21. 235 Collier TJ et al. Presidential symposium: aging and Parkinson's disease: the connection revisited. Cell

Transplant 2008;17:457. 236 Ren ZhenHua & Zhang Yu. Cells therapy for Parkinson's disease - so close and so far away. Sci China

Ser C-Life Sci, 2009. 52(7): 610-614.

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cell therapy will likely ever work! Both supplying more and more L-dopa, only to

have it oxidize and become part of the problem and transplanting stem cells that

may thrive for a while, but then die as well, is like seeing someone shooting at fish

in a fish barrel, the fish dying and their guts spattering everywhere. Is the answer

to stock the barrel with more fish? Or stop the shooter?

The focus of stem cell therapy must be on repairing/replacing mitochondria or 100

years from now we will still be scratching our heads. Of course, prior to stem cell

therapy, the focus must be on the complete elimination of mercury's use in

medicine, dentistry and industry (or at least insomuch as it is then spewed into the

environment).

Nutritional Supplements For Parkinson's

Until such time as a Parkinson's patient can walk into a doctor's office and order a

mitochondrial transplant, powerful preventative and even healing therapy can

come from the right supplements, foods & therapies. We start here with

supplements. Many of the supplements are "polyphenols" discussed in more detail

in the next section. By concentrating food-source polyphenols, a more therapeutic

dose can be achieved. Neurological diseases come about by extraordinary means

as discussed, and extraordinary measures must be taken to counteract the damage.

Phytochemicals, especially polyphenols have been studied by thousands of

researchers. Researchers have found that polyphenols can behave as pro-oxidants

sometimes, and anti-oxidants at other times. For example, polyphenols have been

found to generate reactive oxygen species (like nitric oxide), especially in the

presence of transition metals (like iron), and shown to arrest the proliferation of

tumor cells.237,238

Then at other times polyphenols function either directly or

indirectly as antioxidants.239,240,241

Because the brain is low in natural antioxidant

properties, and high in natural transition metals (iron and copper), supplements

237 CA de la Lastra, I Villegas. Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and

clinical implications. Biochem Soc Trans (2007) 35:1156-1160. 238 KW Lee, HJ Lee. The roles of polyphenols in cancer chemoprevention. Biofactors (2006) 26:105-121. 239 B Frei, JV Higdon. Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr

(2003) 133:3275S-3284S. 240 KE Heim et al. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J

Nutr Biochem (2002) 13:572-584. 241 T. Nakagawa, T Yokozawa. Direct scavenging of nitric oxide and superoxide by green tea. Food Chem

Toxicol (2002) 40:1745-1750.

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have to be chosen carefully. Taking a high concentration of a single supplement

can prove counterproductive at best, and harmful at worst.

A supplement that might appear helpful for one of the things going on might

horribly exacerbate another of the things going on. In neurological diseases,

within the cascade of events stemming from a damaged mitochondria, there are

elevated levels of nitric oxide. For example, a supplement recommended for

Parkinson's because it stimulates dopamine production (just to use as an example)

might also stimulate nitric oxide production, and could therefore be detrimental. In

addition, going to extreme efforts to supply every amino acid or protein compound

known to repair cells can actually exacerbate symptoms and lead to further

suffering, pain, and damage.

Also, when choosing a supplement to combat Parkinson's, does it even get to the

intended target - the brain? Studies following polyphenols within the body find

that metabolism of polyphenols involves absorption in the small intestine, and

processing in the liver to generate active forms that reach the tissues in a form that

can be utilized (glucoronidated, methylated, and sulfated, for example).242

This is

what is meant by a substance being "bioavailable". Once the polyphenol is

bioavailable we run into the issues of uptake by tissues and cells, which varies

from polyphenol to polyphenol. Then comes the issue of whether or not that

bioavailable polyphenol can cross the blood-brain barrier. And, perhaps as a gift

of God and Nature, it has been shown that most polyphenolic compounds are able

to permeate the blood-brain barrier and therefore do their antioxidant magic

directly in the brain.243,244,245,246

Hormetic Pathway - Vitagenes

Some supplements have powerful healing and neuroprotective effects by activation

of hormetic pathways. "Hormesis" means to "set in motion", even impel or urge

242 C Manach et al. Polyphenols: food sources and bioavailability. Am J Clin Nutr (2004) 79:727-747. 243 S. Mandel et al. Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the

treatment of neurodegenerative disorders. Mol Nutr Food Res (2006) 50:229-234. 244 KA Youdim et al. Flavonoids and the brain: interactions at the blood-brain barrier and their

physiological effects on the central nervous system. Free Radic Biol Med (2004) 37:1683-1693. 245 M Mokni et al. Effect of resveratrol on antioxidant enzyme activities in the brain of healthy rat.

Neurochem Res (2007) 32:981-987. 246 MM Abd El Mohsen et al. Uptake and metabolism of epicatechin and its access to the brain after oral

ingestion. Free Radic Biol Med (2002) 33:1693-1702.

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on. Used in physiology, a hormetic pathway is meant to mean that a biological

response has been set in motion against exposure to a toxin or other stressor. In

hormesis, the thought is that a response to low dose toxic insult is generally

favorable, and the response to a high dose toxic insult would generally be

unfavorable - even deadly.247

Homeopathic medicine is based upon the concept of

the body being stimulated into repair mode in response to a low dose toxin.

Of course survival against toxins would depend upon systems within the body

capable of protection and repair. It is a complex system. The part of hormesis that

involves longevity within the body's protection and repair system, consists of

several genes which have been termed "vitagenes". When the vitagenes network

begins to fail, it morphs into a "gerontogene" network, which puts the body on the

pathway to aging.248

Our hope is that with a powerful antioxidant diet,

supplements (including herbs) and lifestyle, we can reverse the hormetic pathway

of gerontogene, back to one of vitagene. This is especially important in our

discussion here on the use of dietary antioxidants in the treatment of

neurodegenerative disorders like Parkinson's. Recent studies show that there are

many phytochemicals that have been found to be protective through the activation

of the vitagenes hormetic pathway.

Bioavailability

Ultimately, finding the purest and most bioavailable form of needed supplements

will be the crucial factor. Consider that when scientists study nutrients in the lab

setting, the nutrient is often injected right near the cell to be tested and the results

then watched and commented upon. Whereas in the body, some substances

injected or taken orally might not reach the cells needing to be effected. One

reason is that the blood-brain barrier keeps many substances out of the central

nervous system (brain, spinal cord and retina). By the way this is not true of most

"phytonutrients", or plant nutrients (directly from the plant foods, eaten in their

natural state), as they are found to cross the blood-brain barrier.

In Parkinson's, it is important to know which supplements are antagonistic to

(oppose) nitric oxide and glutamate. We want to use supplements that are agonistic

247 Calabrese EJ, Baldwin LA. The frequency of U-shaped dose responses in the toxicological literature.

Toxicol Sci (Aug 2001) 62(2):330-338. 248 Sureshi I.S. Rattan. The Nature of Gerontogenes and Vitagenes: Anti-aging Effects of Repeat Heat

Shock on Human Fibroblasts. Annal of the New York Academy of Sciences. Vol. 854. Towards

Prolongation of the Healthy Life Span: Practical Approaches to Intervention 54-60. Nov. 1998.

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to (encourage) endogenous (manufactured within the body) dopamine (both the

production of dopamine and protection of dopamine from oxidation) and increase

endogenous antioxidants like SOD and glutathione without increasing glutamate

activity or nitric oxide. Above all, we want supplements and foods that support

that which heals the mitochondria and the blood-brain barrier.

The goal is not a lot of supplements, but the right supplements. We list most of

the supplements known to be helpful in Parkinson's. Reading through each, you

and your physician can determine which should be a part of your regimen based

upon things like have they been shown to cross the blood-brain barrier, can you get

the substance in foods instead, is the substance available as a supplements, and of

course, should you avoid them because they increase nitric oxide or glutamate.

Acetyl-L-Carnitine an acetylated form of L-carnitine, also called ALCAR

Blood-Brain Barrier acetyl-L-carnitine does cross the blood-brain barrier.

Typical Dose During exercise, portions of L-carnitine and acetyl-coenzyme A are

converted to acetyl-L-carnitine inside the mitochondria by carnitine O-

acetyltransferase.249

L-Carnitine/acetyl-L-carnitine have been demonstrated in the

lab to be neuroprotective through the activation of hormetic pathways, including

vitagenes.250

Alpha-Lipoic Acid - a thiol also called "thioctic acid", abbreviated ALA. This

supplement is widely available in capsule form.

Made up of 2 sulfur atoms and a perhydroxyl radical (HO2)

Blood-Brain Barrier Alpha-Lipoic Acid does cross the blood-brain barrier in a

dosage and frequency dependent manner.251

Typical Dose 200-400 mg./day

249 Zeyner A, Harmeyer J. Metabolic functions of L-carnitine and its effects as feed additive in horses. A

review. Archiv Fur Tierenahrung 52(2):115-138. 250 Vittorio Calabrese et al. Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative

diseases. Frontiers in Bioscience 14, 376-397, January 1, 2009. 376-397. 251 Rooney, James. The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology

of mercury. Toxicology 234(3):145-156.

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Appears to help strengthen a weak blood-brain barrier.252

Converts to various

forms within the body, one of which is an essential cofactor of four mitochondrial

enzyme complexes.253

Reduces tissue levels of nitric oxide and increases

glutathione.254

Also assists in restoring superoxide dismutase, catalase and

myeloperoxidase activity.255

Treatment with lipoic acid prevents oxidative stress

from nitric oxide produced by submitochondrial membranes damaged by

lipopolysaccharide in experimental animals.256

Because of the sulfur, ALA appears

to be a mercury chelator.257

ALA may be more effective than glutathione at removing mercury from the brain,

the body doesn’t produce nearly as much of it as it does glutathione.

Alpha Tocopherol - also known as vitamin E and a-tocopherol.

Blood-Brain Barrier

Typical Dose

Alpha-tocopherol inhibits apoptosis induced by L-glutamine.258

Alpha-tocopherol

along with ubiquinol are found in the mitochondria, and are particularly effective

in scavenging lipid peroxyl radicals as well as preventing the free radical chain

reaction of lipid peroxidation.259

252 Schreibelt G et al. Lipoic acid affects cellular migration into the central nervous system and stabilizes

blood-brain barrier integrity. J. Immunol. 177(4):2630-2637. August 2006. 253 Biewenga G Ph et al. An overview of Lipoate Chemistry, Chapter 1: Lipoic Acid in Health & Disease. 254 Emmez H et al. Anti-apoptotic and neuroprotective effects of alpha-lipoic acid on spinal cord

ischemia-reperfusion injury in rabbits. Acta Neurochir (Wien). June 10, 2010. 255 Saad El et al. Role of oxidative stress and nitric oxide in the protective effects of alpha-lipoic acid and

amino guanidine against isoniazid-rifampicin-induced hepatotoxicity in rats. Food Chem Toxicol. April 22,

2010. 256 Vanasco V et al. The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are

prevented by alpha-lipoic acid. Free Radic Res 2008, Sep;42(9):815-823. 257 Gregus, Z et al. Effects of alpha-lipoic acid supplementation on biliary excretion of glutathione and

metals. Toxicology and Applied Pharmacology 114(1):88-96. 258 Svoboda N, Kerschbaum HH. L-Glutamine-induced apoptosis in microglia is mediated by

mitochondrial dysfunction. Eur J Neurosci 2009 Jul;30(2):1960206. 259

Hazel H. Szeto. Mitochondria-Targeted Peptide Antioxidants: Novel Neuroprotective Agents. The AAPS Journal

2006;8(3) Article 62.

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Daily oral supplementation of a-tocopherol in rats prevented impairment in maze

performance when they were infused with amyloid-beta (a peptide of 39–43

amino acids that appears to be the main constituent of amyloid plaques in the

brains of Alzheimer's disease patients, and Parkinson's disease dementia).260

Ascorbic Acid also known as vitamin C This vitamin is widely available in

supplement form.

Blood-Brain Barrier

Typical Dose

Astaxanthin

Black Tea Extracts

Blood-Brain Barrier

Typical Dose

Black tea extract constituents acted as dietary chelators with the potential to form

complexes mimicking the endogenous antioxidant super oxide dismutase

activities.261

Caffeine

Blood-Brain Barrier

Typical Dose

Pretreatment with caffeine against 6-OHDA-lesioned rats showed that caffeine

attenuated apopmorphine-induced rotational behavior. Apomorphine is used to

260 K Yamada et al. Protective effects of idebenone and alpha-tocopherol on beta-amyloid (1-42)-induced

learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced

neurotoxicity in vivo. Eur J Neurosci (1999) 11:83-90. 261 RK Chaturvedi et al. Neuroprotective and neurorescue effect of black tea extract in 6-

hydroxydopamine-lesioned rat model of Parkinson's disease. Neurobiol Dis (2006) 22:421-434.

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treat "off" episodes (times of difficulty moving, walking, and speaking that occurs

in Patient's with Parkinson's, when their L-dopa wears off.262

Carnosine

Blood-Brain Barrier

Typical Dose

Carnosine has been shown in lab studies to be neuroprotective through the

activation of the vitagenes hormetic pathway.263

Coenzyme Q10 also known as CoQ10, ubiquinone or its more reduced and

active form ubiquinol (a process normally done within the mitochondria). This

supplement is widely available in supplement form.

An oil-soluble substance made within the body, and present in foods as well.

Blood-Brain Barrier Properly emulsified and micellized CoQ10 crosses the blood-

brain barrier. Damage to the mitochondria increases requirements for CoQ10 and

supplementation of forms that will readily cross the blood-brain barrier and

mitochondrial membrane.

Typical Dose 150 mg Ubiquinol equals 1200 mg Ubiquinone264

It was 1200 mg of

Ubiquinone that was found in a 2002 study to reduce the progression of

Parkinson's by 44%.265

Coenzyme Q10 is found in small amounts in foods, but due to mitochondrial

damage , there is a need for therapeutic doses, and so supplementation is

necessary. Coenzyme Q10 is present in most cells, primarily in the mitochondria. It

is part of the electron transport chain across the membrane of the

mitochondria, participating in cellular respiration, and generating energy in the

262 MT Joghataie et al. Protective effect of caffeine against neurodegeneration in a model of Parkinson's

disease in rat: behavioral and histochemical evidence. Parkinsonism Relat D (2004) 10:465-468. 263 Vittorio Calabrese et al. Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative

diseases. Frontiers in Bioscience 14, 376-397, January 1, 2009. 376-397. 264 Yan J, Fuji K et al Reduced coenzyme Q10 supplementation decelerates senescence in SAMP1 mice.

Exp Gerontol. 2006 Feb;41(2):130-140. 265 Clifford W. Shults MD et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing

of the functional decline. Archives of Neurology, 59, No. 10, (October 2002) 1541-1550

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form of ATP. Ninety-five percent of the human body's energy is generated in this

way.266

There are various kinds of Coenzyme Q, but it is Coenzyme Q10 that is

most prevalent in the mitochondria. The 10 refers to a molecular unit that makes

up the molecule and is repeated 10 times. Emulsification and micelle formation is

required for CoQ10's absorption. Micelles are lipid molecules that arrange

themselves in a spherical form in aqueous solutions. This process is mostly done

by secretions from the pancreas and bile salts in the small intestine. Due to poor

absorption across the blood-brain barrier, researchers are rapidly working on a

form that will enter the mitochondria. One formulation that completed its clinical

trials July 2010, is MitoQ produced by Antipodean Pharmaceuticals in New

Zealand. MitoQ is CoQ10 covalently bonded to triphenylphosphonium (TPP+)

cation.267

Creatine increases nitric oxide.

Creatine is a guanidine compound, normally found in urine as a byproduct of

protein metabolism. Creatine is a reservoir for ATP. It is possible that creatine

enables mitochondrial creatine kinase to remain in a stable (octameric) condition to

where mitochondrial permeability transition pore is inhibited, thus blocking cell

death.268

If mitochondrial creatine kinase converts to a less stable (dimeric) state,

the permeability transition pore opens leading to cell death.269

But if this is not the

way creatine prevents cell death, another possibility is that both creatine and

phosphocreatine enhance cytosolic high energy phosphates that maintain ATP

levels during oxidative stress-induced neurodegeneration.270,271

Creatine is made in

the body from other amino acids in the liver, kidney and pancreas. The rest is 266 Dutton PL, et al 4 Coenzyme Q oxidation reduction reactions in mitochondrial electron transport (pp 65-82) in Coenzyme Q: Molecular mechanisms in health and disease edited by Kagan VE and Quinn PJ, CRC Press (2000), Boca Raton 267 Andrew M. James et al. Interaction of the Mitochondria-targeted Antioxidant MitoQ with

Phospholipid Bilayers and Ubiquinone Oxiodoreductases. The Journal of Biological Chemistry. Dec 14,

2006. 268 Dolder M et al. Inhibition of the mitochondrial permeability transition by creatine kinase substrates.

Requirement for microcompartmentation. J Biol Chem 2003;278:17760-17766. 269 O-Gorman E et al. The role of creatine kinase in inhibition of mitochondrial permeability transition.

FEBS Lett 1997;414:253-257. 270 Klivenyi P et al. Neuroprotective mechanisms of creatine occur in the absence of mitochondrial

creatine kinase. Neurobiol Dis 2004;15:610-617. 271

Brustovetsky N et al. On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem

2001;76:425-434.

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obtained from protein foods like poultry and lean red meat. Creatine should

absolutely not be supplemented where there is kidney dysfunction. Excess creatine

can cause the body to lower or stop producing its own.272

Curcumin Botanical name: Curcuma longa L. Chemical name:

diferuloylmethane. A polyphenol found in the root or stem of the herb Turmeric.

This herb is widely available in supplement form.

Blood-Brain Barrier

Typical Dose One study used 80 mg/kg as a therapeutic dose for 3 days (About 4

grams in a 110 pound person)

In the Indian culture, where curcumin is used widely in foods and medicines, there

is a 4.4-fold reduced prevalence in Alzheimer's disease compared to the United

States.273

Curcumin scavenges superoxide anions and nitric oxide radicals274

seen in Parkinson's, and inhibits lipid peroxidation275

. Curcumin protects the

mitochondria from peroxynitrite damage, restores depleted glutathione and

preserves mitochondrial Complex I activity.276

While the toxin paraquat enhances cell death via the production of reactive

oxygen species and thus oxidative stress damage to cells277

, curcumin inhibits

reactive oxygen species, thus protecting against cell death by paraquat.278

Curcumin has been shown in lab studies to be neuroprotective through the

activation of the vitagenes hormetic pathway.279

272 University of Maryland Medical Center. Creatine. http://www.umm.edu/altmed/articles/creatine-

000297.htm 273 M. Ganguli et al. Apolipoprotein E polymorphism and Alzheimer's disease: the Indo-US Cross-National

Dementia Study. Arch Neurol (2000) 57:824-830. 274 Sreejayan N, Rao MN. Nitric oxide scavenging by curcuminoids. Pharm Pharmacol 1997;49:105-7. 275 Sreejayan N, Rao MN. Free radical scavenging activity of curcuminoids. Arzneimittelforschung 1996;

46:169-171. 276 Balusamy Jagatha et al. Curcumin treatment alleviates the effects of glutathione depletion in vitro

and in vivo: Therapeutic implications for Parkinson's disease explained via in silico studies. Free Radical

Biology and Medicine (March 2008) Vol 44, Issue 5. 907-917. 277 Thrash B et al. Paraquat and maneb induced neurotoxicity. Proc West Pharmacol Soc 2007;50:31-42. 278 J. Chen et al. Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced

apoptosis by bcl-2-mitochondria-ROS-iNOS pathway. Apoptosis. 2006;11:943-953.

92 | P a g e

Curcumin reduced amyloid-beta deposits and prevented spatial memory deficits

induced by infusions of amyloid-beta.280

Curcumin is a dietary antioxidant chelator which has shown SOD-like activity.281

Curcumin has a protective effect with routine dietary intake against mercury

exposure.282

Ganoderma Lucidum Reishi Mushroom, Lingzhi This mushroom is widely

available in supplement form.

Blood-Brain Barrier

Typical Dose

This mushroom has been used in traditional Chinese medicine for more than 4,000

years. It has been shown to have anti-bacterial, anti-viral and anti-fungal

properties. 283,284

Microglia were isolated and purified from brains of infant Wistar rats. The

microglia were activated by lipopolysaccharide and MPP+ treated MES 23.5 cell

membranes. In a dose-dependent manner, extract of Reishi mushroom significantly

prevented microglia-derived proinflammatory and cytotoxic factors: Nitric oxide,

tumor necrosis factor-a (TNFa), interlukin 1β (IL-1β). The extract down-regulated

TNFa and IL-1β expression at the mRNA level as well.285

279 Vittorio Calabrese et al. Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative

diseases. Frontiers in Bioscience 14, 376-397, January 1, 2009. 376-397. 280 SA Frautschy et al. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive

deficits and neuropathology. Neurobiol Aging (2001) 22:993-1005. 281 A Bank et al. Evaluation of a new copper(II)-curcumin complex as superoxide dismutase mimic and its

free radical reactions. Free Radical Biol Med (2005) 39:811-822. 282 R Agarwal et al. Detoxification and antioxidant effects of curcumin in rats experimentally exposed to

mercury J Appl Toxicol (Jul 2010) 30(5):457-468. 283 Wang H, Ng TB. Ganodermin, an antifungal protein from fruiting bodies of the medicinal mushroom

Ganoderma lucidum. Peptides (January 2006) 27(1):27-30. 284 Moradali MF et al. Investigation of potential antibacterial properties of methanol extracts from

fungus Ganoderma applanatum. Chemotherapy (2006) 52(5):241-244.. 285 Ruiping Zhang et al. Ganoderma lucidum Protects Dopaminergic Neuron Degeneration Through

Inhibition of Microglial Activation. eCAM 2009 1-9. pbchan@bjsap.org

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Ginkgo Biloba also known as maidenhair tree. Can also be spelled gingko.

This herb is widely available in supplement form.

Blood-Brain Barrier Studies show that after the administration of ginkgo, its

flavonoid metabolites (quercetin, kaempferol and isorhamnetin

derivatives)increase 2-fold in the brain, with about 90% distributed in the

hippocampus, frontal cortex, striatum and cerebellum (38% of the brain).286

Typical Dose The studies have used 50 to 600 mg/kg body weight.

Ginkgo trees are very large, reaching up to over 100 feet and are mostly grown in

China. During the Fall, the tree leaves turn bright yellow, then fall. The trees are

highly resistant to insects and disease, making them very long-lived, with some

trees thought to be up to 2,500 years old!

The female trees produce seeds from which the extract is obtained. This extract

has been found to contain potent antioxidant properties as well as natural

monoamine oxidase B (MAO-B) inhibitor. The terpene lactones and flavonoid

glycosides of ginkgo biloba are credited for its pharmacological actions.

The natural MAO-B inhibitor has been studied for anti-parkinsonian effects in a 6-

hydroxydopamine rat model of Parkinson's. After several weeks on Ginkgo, the

animals' drug-induced symptoms of Parkinson's were significantly (and dose-

dependently) reduced by Ginkgo. Ginkgo restored glutathione as well as the

activities of glutathione-dependent enzymes catalase and SOD in the striatum.

Ginkgo reversed the decrease in number of dopaminergic D2 receptors in the

striatum.287

Ginkgo has been shown to have direct protective effects against mitochondrial

dysfunction in platelets. In the hippocampi, these protective effects were observed

286 Rangel-Ordonez L et al. Plasma Levels and Distribution of Flavonoids in Rat Brain after Single and

Repeated Doses of Standardized Ginkgo biloba Extract EGb 761(R). Planta Med 2010 May 19. Epub. 287 Muzamil Ahmad et al. Ginkgo biloba affords dose-dependent protection against 6-hydroxydopamine-

induced parkinsonism in rats: neurobehavioural, neurochemical and immunohistochemical evidences.

Journal of Neurochemistry, 2005, 93, 94-104.

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only in the elderly. Researchers decided this may be due to an increase in blood-

brain barrier permeability that comes with age.288

Ginsenoside a ginseng saponin derivative from Ginseng. Readily available in

Ginseng supplements.

Blood-Brain Barrier

Typical Dose

Ginsenosides are actually a family of 31 known "triterpene saponins". Each

ginsenoside has been given a label, like Rp1 or Rg1. Ginsenosides from both

American and Asian Ginseng are widely used to manage acute and chronic

inflammatory diseases in Asian cultures.

Ginsenoside Rp1 has been found to exert its powerful antiinflammatory effect due

to inhibition of interleukin-1β production by inhibiting the NF-ӄB pathway.289

NF-ӄB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein

complex that controls the transfer of DNA sequences to mRNA. NF-κB is found

in almost all animal cell types and is also involved in the cell's response to negative

stimuli. As such, NF-ӄB is seen to jump into action during the cascade of events

leading to inflammation both acute and chronic. NF-ӄB is also involved in the

synapsing of neurons.

L-Theanine a non-sulfur amino acid. Also called 5-N-ethyl glutamine. It

differs from glutamine by a CH2-CH3 (ethyl) group. This amino acid is best

obtained from sweet green tea, but is also widely available in supplement form.

Blood-Brain Barrier L-Theanine does cross the blood-brain barrier.290

Typical Dose 20-300 mg/day. It is thought that a cup of tea containing theanine

likely only contains about 5 mg. per cup, but this is difficult to quantify because

288 Shi C et al. Ginkgo biloba extract EGb761 protects against aging-associated mitochondrial dysfunction

in platelets and hippocampi of SAMP8 mice. Platelets. 2010;21(5):373-379. 289 Byung Hun Kim et al. Ginsenoside Rp1, a Ginsenoside Derivative, Blocks Lipopolysaccharide-Induced

Interleukin-1β Production via Suppression of the NF-ӄB Pathway. Planta Med 2009; 75:321-326. 290 Yokogoshi H et al. Effect of theanine, r-glutamylethylamideon brain monoamines and striatal

dopamine release in conscious rats. Neurochem Res 23(5):667-673.

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different green teas have different levels, and the person brewing the tea may steep

it varying lengths of time. Gyokuro is a "sweet green tea" that is supposed to be the

highest quality green tea, and highest in therapeutic compounds.

L-Theanine is either extracted from green tea, or synthesized the same way as in

tea leaves. To synthesize, an ATP added to ethylamine and glutamate yields ADP,

a phosphate and theanine. "Suntheanine" is touted as the purest synthesized L-

Theanine. L-Theanine protects neurons from excess glutamate by blocking

glutamate's entrance into cells, thus it inhibits excitotoxicity seen in neurological

diseases. Decreases nitric oxide production resulting from down-regulated

protein levels of iNOS and nNOS, indicating the inhibition of the NMDA subtype

of glutamate receptors which would account in part for the neuroprotective effect

of L-theanine.291

Attenuates the down-regulation of BDNF and GDNF production

in SH-S&5& cells suggesting a direct neuroprotective action against Parkinson's

disease-related neurotoxicants.292

This is thought to be done, at least in part, by

increasing levels of GABA (gamma-amino-butyric acid) an important inhibitory

neurotransmitter.293

Theanine increases brain dopamine levels as well as has an

affinity for AMPA, kainate and NMDA receptors.294

Caution! It would likely be best for someone with mitochondrial dysfunction, to

get their L-Theanine in its natural form, from high quality sweet green tea.

Isolating L-Theanine, especially taken in the high dose found in supplements, will

likely prove too disruptive to the "good guy" "bad guy" activity of nitric oxide,

lowering the amount needed for healthy cardiovascular function. As with so many

things in Nature, obtaining nutrients in their natural state is best because there are

other compounds designed by Nature to work synergistically with the one nutrient.

L-Theanine, in its natural state is surrounded by polyphenols (flavonols),

291 X Di et al. L-Theanine Protects the APP (Swedish Mutation) Transgenic SH-SY5Y Cell Against

Glutamate-Induced Excitotoxicity via Inhibition of the NMDA Receptor Pathway. Neuroscience (2010). 292 Cho HS et al. Protective effect of the green tea component, L-theanine on environmental toxins-

induced neuronal cell death. 293 Subhuti Dharmananda PhD, Director for Traditional Medicine, Portland, Oregon. Amino Acid

Supplements: Theanine. 294 Nathan P et al. The neuropharmacology of L-theanine (N-ethyl-L-glutamine): a possible

neuroprotective and cognitive enhancing agent. J Herb Pharmacother 6(2):21-30.

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commonly known as the catechins EGCG, EGC, ECG, EC plus caffeine (an

alkaloid) to name a few synergistic compounds.295

NAD

Retinoids And Carotenoids There are two types of vitamin A, retinoids

and carotenoids. These nutrients are best obtained from the diet, but beta-carotene

and vitamin A are widely available in supplement form.

Blood-Brain Barrier

Typical Dose

Retinoids are the fat-soluble form of vitamin A and are found in animal-source

foods like liver, fish oils and butter. Or retinoids can be made within the body just

as they are made in the body of animals that are consumed. Carotenoids are found

in plants like carrots and broccoli, and other dark green, orange, yellow or red

vegetables. Carotenoids also convert to vitamin A in the body, but only as much as

is needed.

Studies have shown that retinoids bind to retinoic acid receptors (RAR) and

peroxisome proliferator-activated receptor (PPAR). RAR and PPAR are ligand-

activated transcription factors which have been recently implicated in the

progression of neurodegenerative and psychiatric diseases. Studies with vitamin A

deprivation have given scientists evidence that retinoic acid signaling is directly

involved in the action and health of motoneurons. 296

Rhodiola Rosea an herb also called Golden Root, Roseroot, Aaron's Rod.

This is an herb that is widely available in supplement form.

Blood-Brain Barrier

Typical Dose

Depressive rats (induced by chronic mild stress) were given 1.5 grams/kg of

Rhodiola rosea extract for three weeks. Their serotonin (5-HT) levels recovered to

295 Chung S. Yang, Zhi-Yuan Wang. The Chemistry of Green Tea.

http://www.teatalk.com/science/chemistry.htm 296 Savien van Neerven et al. RAR/RXR and PPAR/RXR signaling in neurological and psychiatric diseases.

Progress in Neurobiology 85 (2008) 433-451.

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normal status. Researchers concluded that Rhodiola rosea can induce neural stem

cell proliferation at hippocampus to return to normal level, and repair injured

neurons at hippocampus.297

Selenium

Blood-Brain Barrier

Typical Dose

Selenium was protective against 6-OHDA-induced Parkinson's.298

When selenium

was given with or without vitamin E it reduced methyl mercury toxicity.299,300

When selenium as selenite (gypsum) was co-administered, there was a four-fold

protection against methyl mercury over selenate (the sodium salt of selenic

acid).301

It has been found that the protective effect of mercury occurs prior to

absorption.302

Selenium isn't something to be aggressively supplemented, but is

better obtained from the right diet. When administered in conjunction with

inorganic mercury (Hg2+

), selenium protects against mercury toxicity. When

administered alone selenium can methylate to the toxic dimethylselenide.282

Selenium is more efficiently absorbed as selenate than as selenite. (94% versus

59%)303

Selenium in nature doesn't exist alone. Supplements of selenium contain

forms more like those found in nature, most often L-selenomethionine (selenium +

the amino acid methionine). Dietary consumption of selenium reduced the amount

of mercury absorbed from mercury-contaminated fish by 5-11%, but had no effect

on methyl mercury absorption from water.286

297 Q.G. Chen et al. The effects of Rhodiola rosea extract on 5-HT level, cell proliferation and quantity of

neurons at cerebral hippocampus of depressive rats. Phytomedicine 16 (2009) 830-838. 298 KS Zafar et al. Dose-dependent protective effect of selenium in rat model of Parkinson's disease:

neurobehavioral and neurochemical evidences. J Neurochem (2003) 84:438-446 299 J Gailer et al. Structural basis of the antagonism between inorganic mercury and selenium in mammals. Chemical Research in Toxicology, 13, (2000) 1135-1142. 300 P Beyrouty & HM Chan. Co-consumption of selenium and vitamin E altered the reproductive and developmental toxicity of methylmercury in rats. Neurotoxicol Teratol (2006) 301 M Kasuya. Effect of selenium on the toxicity of methylmercury on nervous tissue in culture. Toxicol Appl Pharmacol, 35, (1976)11-20. 302 ML Cuvin-Aralar & RW Furness. Mercury and selenium interaction: a review. Ecotoxicol Environ Saf, 21, (1991)348-364. 303 CD Thomson & MF Robinson Urinary and fecal excretions and absorption of a large supplement of selenium: Superiority of selenate over selenite. Am. J.Clin. Nutr. 44, (1986) 659-663.

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Silymarin Silibinin (also known as silybin) is the major active component in

silymarin, a mixture of flavonolignans* extracted from an herb commonly known

as Blessed Milk Thistle (botanical name Silybum marianum). Lesser known

components of the herb include Silibinin B, isosibilinin A and B, Silicristin and

Silidianin. [*Flavonolignans are polyphenols composed of part flavonoid and part

lignan. Lignans are phytochemicals known as phytoestrogens, which are estrogen-

like chemicals which also act as antioxidants.]

Blood-Brain Barrier

Typical Dose

Silymarin significantly inhibits the LPS-induced activation of microglia

(mediated through the inhibition of nuclear factor kappaB activation) and resultant

production of inflammatory mediators, such as tumor necrosis factor alpha

(TNFa) and nitric oxide. Silymarin effectively reduced LPS-induced superoxide

generation and nuclear factor kappaB (NF-kappaB) activation. This reduced

damage to dopaminergic neurons.304

Tripterygium Wilfordii an herb, also known as Thunder God Vine, is used in

Chinese medicine for everything from fever to carbuncles. Not generally available

in supplement form.

Blood-Brain Barrier

Typical Dose

Triptolide is the active component in the herb Tripterygium Wilfordii that has

been shown to inhibit NF-ӄB transcriptional activity, and thus induce apoptosis in

tumor cells. Triptolide has immunosuppressive, antiinflammatory and antitumor

activity. Because triptolide suppressed the activation of microglia significantly, it

protected dopaminergic neurons from inflammation-mediated damage.305,306

At

medicinal levels of administration, side effects have been lowered production of 304 Wang MJ et al. Silymarin protects dopaminergic neurons against lipopolysaccharide-induced

neurotoxicity by inhibiting microglia activation. Eur J Neurosci 2002 Dec; 16(11):2103-2112. 305 Hui-Fang Zhou et al. Triptolide protects dopaminergic neurons from inflammation-mediated damage

induced by lipopolysaccharide intranigral injection. Neurobiology of Disease 18 (2005) 441-449. 306 Gao JP et al. Triptolide protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic

neurotoxicity in rats: implication for immunosuppressive therapy in Parkinson's disease. Neurosci Bull.

2008 Jun;24(3):133-142.

99 | P a g e

sperm (infertility) and immunosuppression. More studies are needed, as some have

suggested that triptolide may disrupt mitochondrial function in normal cells.

Blocks the production of both tumor necrosis factor alpha (TNFa) and Nitric

Oxide.307

Suppliers of triptolide list it as an immunosuppresant with anti-inflammatory and

anti-tumor properties. They say it is more effective in preventing T cell

proliferation and interferon-y than FK506. They say it is an inducer of apoptosis.

A Diet Rich In Phytochemicals

Phytochemicals are compounds that occur naturally in plants. Polyphenols are just

one of many categories of these chemicals found in plants. Because nearly 6,000

polyphenols have been studied to date, and most have specific, powerful,

protective antioxidant effect in the body, it would be impossible to supplement

them all in pill form. It is therefore absolutely imperative that the diet of someone

with Parkinson's be made up nearly entirely of plant foods, and specifically plant

foods that are grown without pesticides ("organic").

By their very nature, antioxidants would need to be consumed unoxidized for them

to have optimal therapeutic potential. Cooking is the primary way antioxidants

would be oxidized, but so would allowing foods to wither and age. Thus, fruits

and vegetables need to be consumed fresh, and mostly raw for therapeutic value.

307 Feng-Qiao Li et al. Triptolide, a Chinese herbal extract, protects dopaminergic neurons from

inflammation-mediated damage through inhibition of microglial activation. Journal of Neuroimmunology

148 (2004) 24-31.

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News Flash, August 31, 2010. European study found that participants in a study

who ate a diet that was made up of a diverse mix of fruits and vegetables such as

that shown in the photo above, had a lowered risk of a common type of lung

cancer. Head of the project was Dr. H. Bas Bueno-de-Mesquita from the cancer

epidemiology at the National Institute for Public Health and the Environment in

the Netherlands. He explains that a diverse mix means more than just a banana

with your cereal and then cooked carrots and peas with dinner. He says to "think

kale and spinach; berries and melons; cabbage, cauliflower and eggplant..."

There were more than 450,000 adults participating in the nine-year study, from 10

different European countries. Vegetables were divided into categories, like leafy,

fruiting or root vegetables, and did not include legumes, potatoes and other tubers.

Fruits could be fresh, dried or canned, but not included in the computations were

nuts, seeds or olives. When the participants were matched up according to the

diversity of their fruit and vegetable intake, it was shown that smokers who ate the

greatest variety of fruits and vegetables were 27% less likely to develop squamous

cell lung cancer.308

Of course the study concludes with the admonition that

quitting smoking is by far the most important way to lower the risk of lung cancer.

But we also know that more and more people who have never smoked are getting

lung cancer today. So eating a diversity of fruits and vegetables is critical for us

all.

Of course we know that cooking and canning destroys antioxidants. We have to

wonder, if one of the criteria been how many of the fruits and vegetables consumed

were raw, most likely that group would have shown an even higher percentage of

lung cancer avoidance. In fact, in a similar study conducted by the Roswell Park

Cancer Institute in Buffalo, New York, smokers who ate at least 4.5 servings of

raw cruciferous vegetables in a month cut their risk for developing lung cancer by

up to 50%. This begs the question, would daily consumption of raw cruciferous

vegetables cut the risk to nearly 100%? The researchers' comments were that their

findings were consistent with the "biological action of isothiocyanates,

phytochemicals that are abundant in cruciferous vegetables." This study also said

that quitting smoking was by far the best way to prevent lung cancer.

308 H. Bas Bueno-de-Mesquita, M.D., M.P.H., PhD, project director. Cancer Epidemiology, National

Institute for Public Health, Bilthoven, The Netherlands. Marjorie McCullough ScD., strategic director,

nutritional epidemiology, American Cancer Society. Atlanta, September, 2010 Cancer Epidemiology,

Biomarkers & Prevention.

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In addition to destroying antioxidants, cooking foods presents another issue. It has

been said that cooking and aging have similar biological properties. This is

because cooked foods form advanced glycation end products (AGE). Glycation is

when a protein and glucose molecule are bound together, forming irreversibly

damaged protein structures. Many age-related diseases (for example hardening of

the arteries, cataracts, diabetes and neurological diseases) have glycation that

occurs within the body in their etiology. Advanced glycation end products in foods

become glycotoxins and induce the production of a low-grade, but chronic state of

inflammation.309

Of course it is difficult to consume 100% raw foods when you've eaten cooked

foods all your life. Some have done it, but often rely on excessive use of nuts,

seeds, honey and even raw grains to be satisfied. So the "trick" is to eat mostly

raw, and only consume cooked foods that don't generate free glutamates or form

advanced glycation end products. Generally these foods are low in protein or

foods that have been very gently cooked. You have only two food preparation

"rules": Mostly raw (for example two of three meals or 2/3 of every meal) and

whatever you cook or consume cooked must be low in protein and/or cooked

"gently" (low temperatures, short duration). Of course all foods must not have any

free glutamates added.

As you embark upon this way of eating you are going to find that preparing healing

foods on a daily basis is not so much about cooking, but purchasing fresh organic

fruits and vegetables, and preparation. If you're eating correctly, you'll be doing

far more purchasing, washing, cutting up, combining, dressing and a lot of

chewing. But you won't be doing a lot of cooking. When you do cook, it will be

simple - steamed vegetables over rice, dressed with organic extra virgin olive oil

and your favorite herbs is a good example of an acceptable cooked meal.

You probably used to think of fruits as a big bowl of cereal with a few strawberries

on it. Yet what you really need is a big bowl of fresh, organic, raw berries. This

also means that a few leaves of lettuce crowned in a commercial salad dressing

does not suffice as consuming enough therapeutic vegetables. What is needed

every day is an entire bag of organic, raw spinach for the salad, dressed with

organic, extra virgin olive oil, which has its own supply of polyphenols. In fact,

309 Jaime Uribarri et al. Circulating Glycotoxins and Dietary Advanced Glycation Endproducts: Two Links

to Inflammatory Response, Oxidative Stress, and Aging. J Gerontol A Biol Sci Med Sci. (2007 April)

62(4):427-433.

102 | P a g e

there is as much as 5 mg of polyphenols in every 10 grams of olive oil compared to

no polyphenols in most other nut and seed oils you buy in the supermarket.310

The role of phytochemicals, especially "polyphenols", in protecting against

neurological and immunological diseases is the subject of literally thousands of

studies over many decades. It is as if the scientists have feverishly studied

phytochemicals and found amazing and exciting truths, but the "common people"

never got the memo. The most the average person is told is, "eat your vegetables,

they're good for you." Judging by the epidemic of obesity and disease in most

countries today, apparently much more information is needed.

There is a major difference between phytochemicals and man-made chemical

drugs. In fact, of utmost concern when pharmaceutical manufacturers create a

drug to target a particular malfunction in the body, is that the chemical is delivered

to the intended target. Many times these chemicals are found to not get to where

310 http://www.oliveoilsource.com/page/chemical-characteristics

Natural polyphenols can exert protective action on a number of pathological conditions

including neurodegenerative disorders. The neuroprotective effects of many polyphenols

rely on their ability to permeate brain barrier and here directly scavenge pathological

concentration of reactive oxygen and nitrogen species and chelation transition metal ions.

[Katia Aquilano et al. Role of Nitric Oxide Synthases in Parkinson's Disease: A Review on

the Antioxidant and Anti-inflammatory Activity of Polyphenols. Neurochem Res (2008)

33:2416-2426.

A cereal bowl full of organic blueberries and

organic strawberries. A healing afternoon snack.

103 | P a g e

they are needed. Indeed, most of the time, these chemicals do go where they are

not wanted. Hence, we have a list of side-effects as long as your arm for nearly

every drug on the market. Some are extremely frightening ("coma" or "death" for

example). It is a wonder that the pharmaceutical industry is the multi-billion dollar

industry that it is!

Thankfully Nature has taken care of the delivery problem. Powerful, healing

substances, numbering about 6,000 in just the category of polyphenols alone, not

only cross the blood brain barrier when that is where they need to go, but don't

cause the dangerous side-effects that drugs do.

The human body consists of between 10 and 50 trillion cells (apparently no-one

has stayed up late enough to count them definitively). There aren't even 7 billion

people in the world as of 2010. Can you even fathom how many 50 trillion is?

The point is that each and every one of those cells needs protection. Every cell in

your body is being attacked from all sides, every day, by "free radicals" (highly

reactive, unstable molecules, hell-bent on making themselves stable even if it

means destroying your body's cells). Early on we discussed free radicals being

created in Parkinson's mostly in the form of hydrogen peroxide and peroxynitrite,

generated as a result of the damaged mitochondria.

Taking a handful of antioxidant pills, while helpful, is not enough. I repeat,

approximately 6,000 polyphenols have been studied. Each exert their own

mechanism of antioxidant protection. So are your 10-50 trillion cells going to truly

get enough protection when you consume a bowl of sugary cereal with pasteurized

milk, Big Mac, fries, coca cola, Snickers bar, steak and baked potato, and a piece

of pie (sounds like a typical day in the life of the average American to me!) Not

only have you added additional oxidative burden from the foods themselves, but

nowhere in that list of foods is there even a thimble full of protection for your cells

by way of powerful polyphenols. Your 50 trillion cells need more than 50 trillion

little "soldiers" standing guard - every day. The only way you're going to supply

that type of protection is by a diet made up, from dusk to dawn, of whole, mostly

raw, organic plant foods.

Because even nutritionists are often confused, we've inserted a chart of where

polyphenols fit into the family of phytochemicals. As you read through foods and

supplements that are recommended for Parkinson's, you can refer to the chart to

see where that phytochemical fits in. It's truly fascinating. the chart shows that

there are other powerful therapeutic phytochemicals other than polyphenols, and

104 | P a g e

should show us all just how important it is that our diets be made up primarily of

raw plant foods!

Chart Of Phytochemicals

PHENOLIC

COMPOUNDS

Example of

Food(s) Rich in

This

Phytochemical

MONOPHENOLS

Apiole Parsley

Carnosol Rosemary

Carvacrol Oregano

Dillapiole Dill

Rosemarinol Rosemary

FLAVONOIDS also

called Polyphenols

Anthoxantins

Flavonols

Quercetin Onions

Gingerol Ginger

Kaempferol Strawberries

Myricetin grapes

Resveratrol Grapes

Rutin Citrus Fruits

Isorhamnetin Mustard

Flavonones

Hesperidin Oranges

Naringenin Grapefruit

Silybin Milk Thistle Herb

Eriodictyol Lemons

Flavones

Apigenin Celery

Tangeritin Tangerine

Luteolin Green Peppers

Flavan-3-ols also

called Flavanols

Catechins Green Tea

105 | P a g e

Proanthocyanidin

also

called procyanidin

Cocoa

Anthocyanins

Pelargonidin Raspberry

Peonidin Cherry

Cyanidin Red Pears

Delphinidin Bilberry

Malvidin Blueberry

Petunidin Purple Grapes

Isoflavones also called

phytoestrogens

Daidzein Chickpeas

Genistein Legumes

Glycitein Soybeans

Coumestans also

called

phytoestrogens

Various Herbs

Coumestrol Brussels Sprouts

PHENOLIC ACIDS

Ellagic Acid Walnuts

Gallic Acid Mangoes

Salicylic Acid Wheat

Tannic Acid Berries

Vanillin Vanilla Beans

Capsaicin Chili Peppers

Curcumin Turmeric

HYDROXYCINNAMI

C ACIDS

Caffeic Acid Artichoke

Chlorogenic Acid Pineapple

Cinnamic Acid Aloe

Ferulic Acid Oats

Coumarin Corn

LIGNANS also called

phytoestrogens

Silymarin Milk Thistle Herb

Matairesinol Broccoli

106 | P a g e

Secoisolariciresinol Seeds, Carrots

Pinoresinol and

lariciresinol

Sesame Seed

TYROSOL ESTERS

Tyrosol Olive Oil

Hydroxytyrosol Olive Oil

Oleocanthal Olive Oil

Oleuropein Olive Oil

STILBENOIDS

Resveratrol Grapes

Pterostilbene Blueberries

Piceatannol Grapes

TERPENES

[Isoprenoids]

CAROTENOIDS

[tetraterpenoids]

Carotene

Lycopene Tomatoes

Neurosporene Tomatoes

Phytofluene Algae Foods

Phytoene Algae Foods

Xanthophylls

Cryptoxanthin Red Bell Peppers

Zeaxanthin Sweet Yellow Corn

Astaxanthin Microalgae and

Yeast

Lutein Kale, Spinach,

Romaine

MONOTERPENES

Limonene Citrus, Cherries

Perillyl alcohol Citrus Oils, Some

Herbs

SAPONINS

Ginsenosides Panax Ginseng

LIPIDS

Phytosterols Nuts, Seeds, Beans

Campesterol Buckwheat

Beta sitosterol Avocadoes, Nuts,

107 | P a g e

Seeds

Gamma sitosterol Soybeans

Stigmasterol Buckwheat

Tocopherols Vitamin E

Omega 3,6,9 fatty

acids

Dark Green Leafy

Vegetables,

Legumes, Nuts

Gamma-linolenic

acid

Evening Primrose,

Borage, Black

Currant

TRITERPENOID

Oleanolic Acid Garlic, Cloves

Ursolic Acid Cranberries,

Peppermint, Prunes

Betulinic Acid Various Plants Not

Commonly Eaten

Moronic Acid Brazilian Propolis

BETALAINS BETALAINS

Betacyanins

Betanin Beets

Isobetanin Beets

Probetanin Beets

Neobetanin Beets

Betaxanthins

nonglycosidic

versions

Indicaxanthin Beets

Vulgaxanthin Beets

ORGANOSULFIDES

DITHIOLTIONES isothiocyanates

Sulphoraphane Cabbage, Broccoli

THIOSULPHONATES allium compounds

Allyl methyl trisulfide Garlic, Onions

Diallyl sulfide Garlic, Onions

INDOLES,

GLUCOSINOLATES

108 | P a g e

INDOLE-3-

CARBINOL

Mustard Greens

SULFOROPHANE Cabbage, Broccoli

3,3'DIINDOLYLMET

HANE (DIM)

Broccoli

SINIGRIN Broccoli

ALLICIN Garlic

ALLIIN Garlic

ALLYL

ISOTHIOCYANATE

Horseradish

PIPERINE Black Pepper

SYN-

PROPANETHIAL-S-

OXIDE

Onions

PROTEIN

INHIBITORS

PROTEASE

INHIBITORS

Legumes

OTHER ORGANIC

ACIDS

OXALIC ACID Spinach

PHYTIC ACID Inositol

Hexaphosphate

Seeds

TARTARIC ACID Apricots

ANACARDIC ACID Cashews

Specific Foods For Healing

It is thought that what phytochemicals, and especially polyphenols from whole,

raw foods and bioavailable supplements do more powerfully than any drug yet

discovered for Parkinson's, is achieve neuronal protection through reactive oxygen

species and reactive nitrogen species scavenging; metal chelation; and

antiinflammatory actions.

Sweet Green Tea

As mentioned previously, sweet green tea has the highest levels of antioxidants,

and as a bonus, tastes the best, too! Green tea catechins (a family of polyphenols)

109 | P a g e

have been found to be powerfully therapeutic in Parkinson's disease. Yokozawa

showed that green tea catechins protect from peroxynitrite-mediated damage and

prevented 3-nitrotyrosine formation (seen in Parkinson's) better than superoxide

dismutase.311

Green tea catechins have also been shown effective in Parkinson's

therapy due to their ability to chelate iron naturally via preventing redox-active

transition metal from catalyzing free radical formation.312

Green tea catechins is the term to designate the group of catechins in the tea:

Epigallocatechin gallate (EGCG), epigallocatechin (EGC), Epicatechin gallate

(ECG) and epicatechin (EC). The amount of catechins in a cup of green tea is 60

mg. This varies, of course, because green tea comes from leaves of plants which

are subject to growing conditions. Green tea also contains L-theanine, an amino

acid, which is a glutamate antagonist.313,314

Green tea catechins reduce inducible nitric oxide synthase expression and

formation of peroxynitrite. Green tea catechins are also direct scavengers of nitric

oxide and superoxide,315

and have stronger protective activity against

peroxynitrite-induced oxidative damage than the synthetic peroxynitrite scavenger

ebselen316

. In addition green tea catechins protect lipid and proteins against

oxidative modifications in the brain, all of which are seen in Parkinson's.317

311 Yokozawa T et al. ()-Epicatechin 3-O-gallate ameliorates the damages related to peroxynitrite

production by mechanisms distinct from those of other free radical inhibitors. J Pharm Pharmacol (2004)

56:231-239. 312 Weinreb O et al. Neurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's

diseases. J Nutr Biochem (2004) 15:506-516. 313 Shinozaki H, Ishida M. Theanine as a glutamate antagonist in crayfish neuromuscular junction. Brain

Res. 1978 Jul 28;151(1):215-9. 314 X Di et al. L-Theanine Protects the APP (Swedish Mutation) Transgenic SH-SY5Y Cell Against

Glutamate-Induced Excitotoxicity via Inhibition of the NMDA Receptor Pathway. Neuroscience. 2010 Jul

14;168(3):778-86. 315 T Nakagawa, T Yokozawa. Direct scavenging of nitric oxide and superoxide by green tea. Good Chem

Toxicol (2002) 40:1745-1750. 316 T Yokozawa et al. ()-Epicatechin 3-O-gallate ameliorates the damages related to peroxynitrite

production by mechanisms distinct from those of other free radical inhibitors. J Pharm Pharmacol (2004)

56:231-239 317 Keiko Unno and Minoru Hoshino. Brain Senescence and Neuroprotective Dietary Components.

Central Nervous System Agents in Medicinal Chemistry 2007, 7, 109-114.

110 | P a g e

Green tea catechins also have the ability to chelate excess iron, a factor in

Parkinson's. Of course, when excess iron is lessened, it is prevented from

catalyzing free radical formation.318,319

Muscadine Grapes

Muscadine Grapes contain up to six times more resveratrol, found mostly in the

skin and seeds, than any other grape. When high doses of resveratrol was given to

fish, their lifespan increased by 56%.320

When high doses have been given to

animals in various studies resveratrol inhibited cancer, was a powerful

antioxidant, was effective against neuronal cell dysfunction and more.

Resveratrol was found to potently reduce LPS-induced PGE2 synthesis and the

formation of 8-iso-PGF2a' a measure of free radical production. Resveratrol

reduced the expression of mitochondrial RNA and protein of mPGES-1, a key

enzyme responsible for the synthesis of PGE2 by activated microglia, while not

affecting COX-2 (the first known inhibitor to do this).321

Unfortunately, these

studies have been done only in animals thus far.

Resveratrol given to 6-hydroxydopamine (6-OHDA) induced Parkinson's disease

rats showed reduced behavioral, biochemical and histopathological changes caused

by free radicals. Immunohistochemical findings in the substantia nigra showed

that resveratrol protected neurons from the deleterious effects of 6-OHDA.322

Resveratrol inhibits hippocampal cell death induced by trauma or ischemia, and

intracellular reactive oxygen species formation.323,324,325

318 O Weinreb et al. Neurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's

diseases. J Nutr Biochem. (2004) 15:506-516. 319 S. Mandel, MB Youdim. Catechin polyphenols: neurodegeneration and neuroprotection in

neurodegenerative diseases. Free Radic Biol Med (2004) 37:304-317. 320 Valenzano DR et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a

short-lived vertebrate. Current Biology (2006) 16(3):296-300 321 Eduardo Candelario-Jalil et al. Resveratrol potently reduces prostaglandin E2 production and free

radical formation in lipopolysaccharide-activated primary rat microglia. Journal of Neuroinflammation.

20074:25. 322 MM Khan et al. Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine

depletion in rat model of Parkinson's disease. Brain Research. 2010 Apr 30;1328:139-151 323 KT Lu et al. Neuroprotective effects of resveratrol on cerebral ischemia-induced neuron loss mediated

by free radical scavenging and cerebral blood flow elevation. J Agric Food Chem (2006) 54:3126-3131.

111 | P a g e

Resveratrol participates in protecting against brain damage from excitotoxicity326

(primarily excess glutamate activity leading to excess nitric oxide production).

Resveratrol protected rat primary neurons against the expression of caspases 3 and

12 and calcium overload thus inhibiting apoptosis.327

Resveratrol inhibits oxidized dopamine's activation of caspases (which leads to the

degeneration of dopaminergic neurons), strongly enhancing the expression of the

anti-apoptotic protein Bcl-2.328

Because studies showed that resveratrol protected against rotenone toxicity

(which acts primarily by inhibiting the electron transport chain at complex I of the

mitochondria), researchers conclude that resveratrol would be protective in

counteracting the mitochondrial production of reactive oxygen species at both the

cytosolic (the liquid found inside of cells) and mitochondrial level.329

An extract of whole grape exhibited dose-dependent scavenging effects of reactive

oxygen species in fruit flies. The extract also inhibited increases of reaction

oxygen species when rat liver mitochondria were exposed to a potent lipid oxidant

generator. The extract protected enzyme activities of the mitochondrial respiratory

electron transport chain, complexes I and II. Researchers concluded that whole

324 U Sonmez et al. Neuroprotective effects of resveratrol against traumatic brain injury in immature

rats. Neurosci Lett (2007) 420:133-137. 325 S Bastianetto et al. Neuroprotective abilities of resveratrol and other red wine constituents against

nitric oxide-related toxicity in cultured hippocampal neurons. Br J Pharmacol (2000) 131:711-720. 326 M Virgili, A Contestabile. Partial neuroprotection of in vivo excitotoxic brain damage by chronic

administration of the red wine antioxidant agent, trans-resveratrol in rats. Neurosci Lett (2000) 281:

123-126. 327 QH Gong et al. Inhibition of caspases and intracellular free Ca2+ concentrations are involved in

resveratrol protection against apoptosis in rat primary neuron cultures. Acta Pharmacol Sin (2007)

28:1724-1730. 328 MK Lee et al. Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine.

Exp Mol Med (2007) 39:376-384. 329 Unpublished data from K. Aquilano et al. Department of Biology, University of Rome "Tor Vergata",

Via della Ricerca Scientifica, 00133 Rome, Ital. email: ciriolo@bio.uniroma2.it

112 | P a g e

grape extract with resveratrol is a potent mitochondrial protector, and thus a

candidate to protect against neurodegenerative diseases like Parkinson's.330

In healthy animals resveratrol significantly dose-dependently increased levels of

superoxide dismutase, catalase and peroxidases.331

Studies on bioavailability in humans have shown that resveratrol was found to be

poorly absorbed in pill form because as it passes through the intestines where it

conjugates with glucuronate and sulfonate.332

Even when a very large dose of

resveratrol was given (2.5 and 5 grams), the amount that showed up in the blood

was far below what would be necessary to do what was seen in the animal

studies.333

Because of poor absorption, resveratrol was given as a sublingual supplement, to

allow for direct absorption through the mucosa of the mouth. When 1 mg of

resveratrol (in a 50 ml solution) was held in the mouth for one minute before

swallowing, 37ng/ml of free resveratrol was measured in plasma two minutes later.

To achieve the same thing with pill form, 250 mg of resveratrol would need to be

taken.334

It appears Nature knows best again, as chewing grapes and allowing the

juice to bathe the inside of the mouth appears to be the best way to obtain

resveratrol!

If you do supplement resveratrol, you want to find one that is 99% Trans-

resveratrol and free of emodin. Emodin is a "purgative resin" - a chemical

naturally present in some plants that can cause diarrhea.

Mangoes

330 Jiangang Long et al. Grape Extract Protects Mitochondria from Oxidative Damage and Improves

Locomotor Dysfunction and Extends Lifespan in a Drosophila Parkinson's Disease Model. Rejuvenation

Research. Vol 12, No 5 (2009) 321-331. 331 M Mokni et al. Effect of resveratrol on antioxidant enzyme activities in the brain of healthy rat.

Neurochem Res (2007) 32:981-987. 332 Walle T et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug

Metabolism and Disposition. (2004) 32 (12):1377-1382. 333 Boocock DJ et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol,

a potential cancer chemopreventive agent. Cancer Epidemiology, Biomarkers & Prevention (June 2007)

16(6):1246-1252. 334 Asensi M et al. Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free

Radical Biology & Medicine (August 2002) 33(3):387-398.

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Mangoes contain mangiferin, a polyphenol studied as an antioxidant for

Parkinson's. Mangiferin was shown to reverse oxidative stress likely through its

scavenging activity against reactive oxygen species. When Parkinson's is induced

in lab animals using the toxin MPTP, mangiferin protects against cytotoxicity.335

Mangiferin crosses the blood-brain barrier which is absolutely essential if it is to be

of any use in Parkinson's.336

Garlic

Sulfur compounds found in garlic have been found to protect against MPTP

toxicity.337

Soybeans

Soybeans contain a substance called genistein that has been found to protect

dopaminergic neurons by inhibiting microglial activation (inflammation in the

brain). Genistein is the primary soybean isoflavone. In a "concentration-

dependent" manner genistein counteracted lipopolysaccharide-induced decrease in

dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons.338

Biochanin A, also in soy also protects dopaminergic neurons against

lipopolysaccharide-induced damage through inhibition of microglia activation, and

thus proinflammatory factors.339

It is extremely important to make it clear here that soybeans must only be eaten in

their whole, unprocessed state. When soybeans are processed in any way, high

amounts of free glutamates are generated. Soybeans can be healthful whole, but

are disease contributing in their processed state.

335 Amazzal L et al. Mangiferin protects against 1-methyl-4-phenylpyridinium toxicity mediated by

oxidative stress in N2A cells. Neurosci Lett (2007) 418:159-164. 336 Martinez G et al. Effect of Mangifera indica L. extract (QF808) on protein and hepatic microsome

peroxidation. Phytother Res (2001)15:581-585. 337 Liu KL et al. DATS reduces LPS-induced iNOS expression, NO production, oxidative stress, and NF-

kappaB activation in RAW 264.7 macrophages. J Agric Food Chem (2006) 54:3472-3478. 338 Xijn Wang et al. Genistein protects dopaminergic neurons by inhibiting microglial activation.

NeuroReport Vol 16 No 3 (February 2005) 267-270. 339 Han-Qing Chen et al. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced

damage through inhibition of microglia activation and proinflammatory factors generation Neuroscience

Letters 417 (2007) 112-117

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Tomatoes

Tomatoes contain carotenoids, like lycopene which have been found to

counteract mercury's toxic effects on cells, in particular the release of cytokines

like TNFa.340

Diagnostic Tests

Mercury Testing

You cannot test for mercury in hair341

or blood. Mercury becomes lodged in the

brain, bone and other tissue and won't be discerned by typical testing.

Mitochondrial Dysfunction Tests

Typical tests screen for disorders of oxidative phosphorylation342

. Normal results

do not exclude a mitochondrial disorder, however.

Fasting Blood Test Complete blood count, comprehensive metabolic panel,

creatine kinase, Vitamin B12, methylmalonic acid, leukocyte CoQ10, acylcarnitine

profile, ammonia*, lactic acid*, pyruvic acid*, plasma amino acids. [*prone to

sample handling/acquisition errors]

Urine Test Taken As First Morning After Fasting pH, organic acids, amino acids,

acylcarnitine profile.

Red Flags increased lactate/pyruvate ratio, decreased serum bicarbonate, increased

CK or AST (suggestive of mild metabolic muscle disorder), decreased carnitine,

short chain dicarboxylic fatty acids seen on urine organic acid screen (suggests

mitochondrial beta oxidation defect), urine organic acids also showing increased

fumarate, malate, 3-methylglutaconate, increase alanine relative to lysine* (more

stable surrogate marker of pyruvic acid seen on plasma and urine amino acid

panels), increased glycine, or proline. [*alanine/lysine ratio is believed by some

340 Zefferino R et al. Mercury modulates interplay between IL-1beta, TNFalpha, and gap junctional

intercellular communication in keratinocytes: mitigation by lycopene. J Immunotoxicol 2008

Oct;5(4):353-360. 341 AS Holmes, BE Haley et al. Reduced Levels of Mercury in First Baby Haircut of Autistic Children.

International Journal of Toxicology (2003) 22:227-285. 342 Jon S. Poling MD, PhD. Mitochondrial Disorders and Autism. Athens Neurological Associates. July 12,

2008.

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experts to be the best non-invasive indicator of oxidative phosphorylation disorder;

however, unless specifically calculated (normal ratio 1.5 to 2.5) by the ordering

physician, the report will come back as normal from the reference laboratory on

routine amino acid reports.]

MitoSciences sells Monoclonal Antibody Tests, Enzyme Activity Assays, Protein

Quantity Assays, Multiplexing Arrays and Enzyme Purification Kits all for the

purpose of testing for Complex I dysfunction. 343

Elevated Inflammatory Cytokines tumor necrosis factor (TNFa) and IL-6 are the

best evidence of neuroinflammation in Parkinson's disease patients.344

Clinical Mitochondrial Therapies

[ ] DMSA For Mercury Chelation

DMSA (Dimercapto succinic acid) is a sulfhydryl-containing, water-soluble, non-

toxic, orally administered metal chelator because it has a high affinity for metals

like mercury because of the sulfhydryl group, just like that found in the

mitochondrial membrane. However, DMSA has been shown to not cross the

blood-brain barrier. In addition, in people with compromised kidney function,

DMSA (and many other chelating agents) might redistribute the mercury, dropping

mercury back into the body when the kidneys aren't able to properly excrete the

mercury quickly enough. As it also so happens, mercury is toxic to all organs,

especially the kidneys.345

[ ] Intravenous Ginkgo

Researchers administered 8 mg/kg "bilobalide" to rats and found a significant level

of bilobalide in both plasma and brain.346

343 MitoSciences, 1850 Millrace Drive, Suite 3A, Eugene, Oregon 97403. (541) 284-1800.

sales@mitosciences.com. 344 H. Wilms et al. Inflammation in Parkinson's diseases and other neurodegenerative diseases: cause

and therapeutic implications. Curr Pharm Des (2007) 13:1925-1928. 345 Rudolfs K. Zalups. Molecular Interactions with Mercury in the Kidney. Pharmacological Reviews.

March 1, 2000. Vol 52. No 1. 113-144. zalups.rk@gain.mercer.edu 346 Madgula VL et al. Intestinal and blood-brain barrier permeability of ginkgolides and bilobalide: in vitro

and in vivo approaches. Planta Med 2010 Apr;76(6):599-606.

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[ ] Methylcobalamin, Folate and B6

Vitamin B12 is needed in the synthesis of S-adenosylmethionine (SAMe). SAMe is

a "methyl donor". Methyl donors are needed in monoamine neurotransmitter

metabolism, receptor systems, and remyelination. It is currently thought that

impaired methylation contributes to neurological disorders.347

The use of

Levodopa is known to increase the consumption of S-adenosylmethionine.348

Researchers have found that when there is a deficiency of B12, homocysteine is

neurotoxic as it interacts with nitrite (a metabolite of nitric oxide) and glutamic

acid (glutamate) in Parkinson's patients treated with levodopa. Thus, increased

homocysteine levels may accelerate dopaminergic cell death in Parkinson's

disease. They suggest higher daily intakes of Vitamin B12, folate and Vitamin

B6.349

[ ] Mitochondria-Targeted Peptide Antioxidants

In a healthy body, endogenous mitochondrial antioxidants, like mitochondrial

glutathione peroxidase, breaks H2O2 down to water. Two other mitochondrial

antioxidants, thioredoxin and glutaredoxin, are thiol-disulfide antioxidants (a red

flag with mercury's name on it should go off whenever you see "thiol" of

"sulfide"). Two antioxidants, more familiar to most people, present in the

347 T Bottiglieri et al. The clinical potential of ademetionine (S-adenosylmethionine) in neurological

disorders. Drugs (Aug 1994) 48(2):137-152. 348 Orozco-Barrios CE et al. Vitamin B12-impaired metabolism produces apoptosis and Parkinson

phenotype in rats expressing the transcobalamin-oleosin chimera in substantia nigra. PLoS One (Dec 21,

2009) 4(12):e8268. 349 GA Qureshi et al. Is the deficiency of vitamin B12 related to oxidative stress and neurotoxicity in

Parkinson's patients? CNS Neurol Disord Drug Targets (Feb, 2008) 7(1):20-27.

It is now appreciated that reduction of mitochondrial oxidative stress may prevent or

slow down the progression of these neurodegenerative disorders. However, if

mitochondria are the major source of intracellular ROS and mitochondria are most

vulnerable to oxidative damage, then it would be ideal to deliver the antioxidant therapy

to mitochondria. [Hazel H. Szeto. Mitochondria-Targeted Peptide Antioxidants: Novel

Neuroprotective Agents. The AAPS Journal 2006;8(3) Article 62.

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mitochondria are a-tocopherol (vitamin E) and ubiquinol (Coenzyme Q10). In a

healthy body, these more familiar antioxidants are very good at getting rid of lipid

peroxyl radicals, thus preventing the peroxidation of lipids (fats). One lipid

needing major protection is cardiolipin, the major phospholipid on the

mitochondria inner membrane. Cardiolipin is highly susceptible to peroxidation

because it is highly unsaturated, which means it has many sites on its molecule

which are easily oxidized.350

We know that cardiolipin is associated with

cytochrome c. When cardiolipin is oxidized, cytochrome c is released through the

outer mitochondrial membrane, something also seen in Parkinson's.351

When cytochrome c is released from the mitochondria into the cytoplasm, it

initiates a cascade of events involving caspase 9, 3 & 7 (proteases which are

involved in apoptosis) known to do damage to components within the cell352,353

all

leading to what is called the intrinsic mitochondrial pathway of apoptosis.

Excessive depletion of ATP results in cell death. Of course, it is the death of

dopaminergic neurons that is what causes the symptoms of Parkinson's.

SS Antioxidants

The statement is made that mitochondria undergo oxidative damage when reactive

oxygen species production exceeds the antioxidant capacity of mitochondria, and

this is true. What is missing, however, is that mercury initiates mitochondrial

damage, as if mitochondria simply "self destruct" or at least "mysteriously"

destruct. This is critically important because current efforts to cure Parkinson's

focus almost solely on the reactive oxygen species being created by a

dysfunctional, damaged mitochondria. Therapies need to be aimed in two places:

completely eliminating mercury exposure and repair of mitochondria. This is truly

a radical shift in focus, but a shift that must be made if we are ever to "cure"

Parkinson's.

If simply taking a-tocopherol, CoQ10 and green tea polyphenols were completely

effective in humans, we would have cured Parkinson's long ago. Yet all of these

350 Laganiere S, Yu BP. Modulation of membrane phospholipid fatty acid composition by age and food

restriction. Gerontology. 1993;39:7-18. 351 Shidoji Y et al. Loss of molecular interaction between cytochrome c and cardiolipin due to lipid peroxidation. Biochem Biophys Res Commun . 1999; 264:343-347. 352 Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309-1312. 353 Li P, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an

apoptotic protease cascade. Cell. 1997;91:479-489.

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antioxidants, and many others have been shown to have powerful effects against

the free radicals produced in Parkinson's models in animals.354

Unfortunately,

most substances tested in labs and animals have failed to show benefits in humans.

As we discussed earlier, aiming a nutrient at a cell in a Petri dish, almost never

translates to the same effect within a living, diseased human body. The reasons are

likely too numerous to elaborate upon here, but a few are the blood-brain barrier,

"rebound" effects within the human body, and bioavailability of substances, i.e.,

can the substance do what it is supposed to within the "environment" it finds itself

in, in a human body.

If we are going to have any effect upon the extreme free radical damage occurring

in Parkinson's, our therapies are going to have to target the mitochondria. This

means that the compounds must be able to cross the blood-brain barrier, and the

mitochondrial inner membrane.

This all brings us to "SS antioxidants" (Szeto-Schiller). The previously mentioned

MitoQ is the mitochondrially-targeted peptide antioxidant SS-31. How do these

antioxidants work?

Because there is a higher concentration of protons outside the inner membrane of

the mitochondria than inside the membrane a negative potential of 150 to 180

millivolts is generated across the mitochondrial inner membrane. Therefore,

lipophilic (attracted to fats) cations (an ion with more protons than electrons,

giving it a positive charge) are highly attracted to the mitochondrial matrix. And

indeed, when antioxidants are made into lipophilic cation compounds, they

accumulate 100 to 1000-fold in the mitochondrial matrix.355

The mitochondrial

matrix contains the mitochondria's DNA and is where much activity of the

mitochondria takes place.

How are antioxidants transformed into those that will target the mitochondria? By

conjugating it to a lipophilic cation, such as triphenylphosphonium (TPP+).

Coenzyme Q10 and Vitamin E, when combined with TPP+

were found to

preferentially accumulate in the mitochondrial matrix. MitoVitE was reported to

354 Beal MF, Mitochondria, oxidative damage, and inflammation in Parkinson's disease. Ann NY Acad Sci.

2003;991:120-131. 355 Matthias L. Jauslin et al. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts

from endogenous oxidative stress more effectively than untargeted antioxidants. The FASEB Journal

August 15, 2003. mpm@mrc-dunn.cam.ac.uk Michael P. Murphy

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be 800-fold more potent than idebenone (a drug for Alzheimer's with properties

similar to CoQ10) in protecting against glutathione depletion. MitoVitE was 350-

fold more potent than trolox (a water-soluble derivative of vitamin E).

MitoQ and MitoVitE inhibited H2O2-induced apoptosis in endothelial cells.356

In keeping with all natural functions in the body, there is a "homeostasis" within

the mitochondria, seeking a proper balance of all substances and functions. In fact,

it has been found that more is not better when it comes to these mitochondria-

targeted antioxidants. The mitochondria will self-limit the uptake of the

antioxidants at concentrations greater than 50 μM (50 micrometres).357

Too high of

concentrations of MitoQ, for example, have been shown to cause mitochondrial

depolarization.358

Excited about the possibilities, a one year, double-blind, placebo-controlled study

to assess Mito-Q's function as a disease-modifier in Parkinson's was completed in

July of 2010. The study was conducted in 13 clinics in New Zealand and

Australia, on idiopathic Parkinson's disease patients who were taken off of all

medications. Patients were given MitoQ at 40 or 80 mg or a matching placebo. At

the end of the study the researchers concluded that MitoQ did not slow the

progression of untreated Parkinson's according to their UPDRS359

and other

measurement scales. When I inquired about MitoQ, I was told, "MitoQ failed".

The researchers surmised that the sample size was too small, or that the outcome

measures were inappropriate.360

I would like to suggest that with everything that has been outlined in this book, Co-

Enzyme Q10 alone would not stop the progression of Parkinson's. However, I

356 Anuradha Dhanasekaran et al. Supplementation of Endothelial Cells with Mitochondria-targeted

Antioxidants Inhibit Peroxide-induced Mitochondrial Iron Uptake Oxidative Damage, and Apoptosis. The

Journal of Biological Chemistry. September 3, 2004. Vol. 279. 37575-37587. 357 Smith RA, et al. Selective targeting of an antioxidant to mitochondria. Eur J Biochem . 1999; 263 :709-716 . 358 Kelso GF et al . Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem . 2001 ; 276:4588-4596 . 359 http://www.mdvu.org/library/ratingscales/pd/updrs.pdf 360 Barry J. Snow MD et al. A Double-Blind, Placebo-Controlled Study to Assess the Mitochondria-Targeted Antioxidant MitoQ as a Disease-Modifying Therapy in Parkinson's Disease. Movement Disorders ahead of publication, August 2010. Correspondence to: Dr. Barry J. Snow, Neurology Department, Auckland Hospital, Auckland, New Zealand. E-mail: bsnow@adhb.govt.nz

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would fully expect that MitoQ would supply an important part of the solution, and

should not be given up on. Making sure mercury and any other toxins are

eliminated, along with the right polyphenol-rich diet, and the addition of missing

antioxidants and nutrients (like MitoQ) along with reparative stem cells would

likely yield the results these researchers were looking for.

RESOURCES

Muscadine grapes can be grown easily, so they say. Vines, well on their way to

producing grapes, can be purchased online at www.isons.com.

ACTUALLY SEEN IN THE SUBSTANTIA NIGRA OF

PARKINSON'S PATIENTS

Increased nitrotyrosine was detected in the substantia nigra of in vivo models of

Parkinson's

High levels of neuronal and inducible nitric oxide synthase were found in the

substantia nigra of patients

a-synuclein is found to be highly expressed in the substantia nigra of Parkinson's

patient's