Treatment of Parkinson’s Disease

Christopher BuchananCHEM 5398/Buynak

April 3, 2007

Parkinson’s Disease Overview

• Prevalence: 0.3% of U.S. Population– Increases to 4-5% for those 85 years

old and older

• Dopaminergic degeneration in the substantia nigra– in the deep gray matter of the brain– Basal ganglia produce less dopamine

Parkinson’s Overview (cont’d)

• Symptoms:– Bradykinesia (slowed movements)– Resting tremor– Rigidity

• Other Neurotransmitters are affected– Non-Adrenergic, Serotinergic, and Cholinergic

neurons are lost– Results in: cognitive decline, sleep

abnormalities, depression, gastrointestinal and genitourinary problems

– Usually Seen in Later Stages of Parkinson’s

Therapy

• Therapy should begin when normal functions are impaired to due to symptoms (i.e. limits daily activities)– Therapy must be individualized based

on progression and time of onset

• Therapies vary depending on age of onset, progression of symptoms, and side-effects of drugs

Medicinal Therapy

• Levadopa (L-DOPA)– Still the preferred medication to control

Motor symptoms– Used in combination with Carbidopa to

prevent premature decarboxylation• Drug: Sinemet

HO

HO

HN

CO2H

NH2

H3C

HO

HO

NH3+

O O

H

L-DOPA Carbidopa

L-DOPA

-Adapted from Presentation Slide from Dr. John Buynak

• Levodopa is decarboxylated to form dopamine, thus replenishing the dimished supply

• Dopa Decarboxylase is saturated at 70 to 100 mg/day

HO

NH2

CO2H

L-Tyrosine

Tyrosine

hydroxylase HO

NH2

CO2H

Levodopa(L-DOPA)

HO

HO

NH2

Dopamine

HODopa

Decarboxylase

Dopamine

β-hydroxylase

HO

HO

NH2

OH

Norepinephrine(Noradrenaline)

HO

HO

NHMe

OH

Epinephrine(Adrenaline)

N-methyl transferase

(in Adrenal medulla)

L-DOPA

• Downsides– Continual use can lead to motor

complications (dyskinesia), which must be treated

– This can be somewhat offset by lowering the dosage

• This is an important factor for patients with Early Onset Parkinson’s Disease

Dopamine Agonists

• Directly stimulate dopamine receptors

• Bromocriptine (Perlodel)

• Pergolide (Permax)

wikipedia http://en..org/wiki/Parlodel

http://en.wikipedia.org/wiki/Pergolide

Dopamine Agonists

• Often used in combination with Levadopa

• Studies have shown that its use alone delays or lowers the incidence of motor complications associated with the use of Levadopa

• Often prescribed to patients with mild disease at a younger onset age

Late Stage Parkinson’s

• Seen in 40% of Patients having received Levadopa treatment for 5+ years– Motor complications usually arise

• Patients experience a “wearing off” effect– Each dose of levadopa has a shorter duration

of effect

• Motor Complications treated with:– Dopamine Agonists, MAO-B Inhibitors, COMT

Inhibitors

MAO-B Inhibitors

• MAO = monoamine oxidase

-Oxidative deamination

• Reduce disability and delay need for Levadopa– Believed to be somewhat neuroprotective

H R-C-NH2 + O2 + H2O → R-C=O + NH3 + H2O2 H H

MAO-B Inhibitors

• Selegiline (Eldepryl)

• Rasagiline (Azilect)

http://en.wikipedia.org/wiki/Selegiline

http://en.wikipedia.org/wiki/Rasagiline

COMT Inhibitors

• COMT: catechol O-methyltransferase• Inhibition increases the half life of Levadopa -->

decreases “Off” times• Tolcapone (Tasmar):

• Monitored closely due to rare side effect of fatal hepatotoxicity

http://en.wikipedia.org/wiki/Tolcapone

COMT & MAO Inhibitors

http://en.wikipedia.org/wiki/Image:Dopamine_degradation.svg

New Therapeutic Approaches

• Glial Cell-line-Derived Neurotrophic Factor (GDNF)– Shown to aid degenerating neurons– However, there is very little evidence to

support it’s widespread use• Adenosine Antagonists

– Colocalized with striatal dopamine (D2) receptors

– Studies show that they often reverse motor defects from Parkinson’s

Novel Approaches

• N-methyl-D-Aspartate (NMDA) Receptor Antagonists– Shown to reduce motor complications

from L-DOPA therapy– Amantadine (Symmetrel):

http://en.wikipedia.org/wiki/Amantadine

Surgical Therapies

• Deep Brain Stimulation– With precise brain mapping, stimulation

of the subthalamic nucleus can be performed

– Improves motor function– Reduces dyskinesia and need for

medications– Downfall: often causes destructive

lesions

Interesting Observations

• An inverse relationship between smoking and Parkinson’s has been demonstrated– Mechanism of protection (if any) is

unknown

• Consuming Caffeine (an adenosine antagonist) has been linked with a lesser risk of developing Parkinson’s

Sources

Figures: Wikipedia.org

Schapira, Anthony H., Bezard, Erwan, et. al “Novel Pharmacological targets for the treatment of Parkinson’s Disease.” Nature Reviews: Drug Discovery. 5 (2006): 845-854.

Rao, Shobha A., Hoffman, Laura A., and Shakil, Amer. “Parkinson’s Disease: Diagnosis and Treatment.” American Family Physician. 74 (2006): 2046-2054

Jankovic, Joseph. “An Update on the Treatment of Parkinson’s Disease.” Mount Sinai Journal of Medicine. 73 (2006): 682-689