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Illn
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su
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to b
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ssoci
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dw
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oxid
ati
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tress
Eye Brain
Chest
Lower abdomen
Abdomen
Body
Air tubeFace
Radiation
UV radiation
Smoking
Air pollutants
Agriculturalchemicals
Additives
DetergentsActivated oxygen
Free radicals
AntioxidantsVitamin E
Vitamin C-Carotene
FlavonoidsUbi qui none
Scavenging
http://www.hsrmagazine.com/arti2cles/ c
1specialty2.html
ORAC=Oxygen Radical Absorbance Capacity
Blackcurrant
Strawberry
Raspberry
“Antioxidants! Antioxidants!….”
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50
40
30
20
10
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Year 1994 1995 1996 1997 1998 1999
% 11.9 19.7 13.2 24.1 29.3 30.6
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1.Generation of free radicals, oxidative stress ddd ddddd ddddddd& ’ : ศ.ดร้. ไมตร้� สี"ที่ธจ�ตต�
4 .Antioxidants in cosmetics:ร้ศ.ดร้. พร้ร้ณว�ภัา กฤษฏาพงศ�
3 .Antioxidants in neurodegenerativeddddddddd: ร้ศ.ดร้. จ�นตนา สี�ตยาศ�ย
2 .Antioxidants in metabolic disorders: ร้ศ.ดร้. ว�ร้พล ค!%คงว�ร้�ยพ�นธ�
ร้ศ.ดร้ . จ�นตนา สี�ตยาศ�ยภัาคว�ช้าเภัสี�ช้ว�ที่ยาคณะแพที่ยศาสีตร้�มหาว�ที่ยาล�ยขอนแก%น
• สีมองม�ปีร้�มาณไขม�นไม%อ�$มต�ว (PUFAs) เปี2นจ3านวนมากที่3าให�ไว ต%อภัาวะเคร้�ยดที่างออกซิ�เดช้�น• สีมองใช้�ออกซิ�เจนในอ�ตร้าที่�$สี!งมาก จ5งม�การ้ปีล%อย oxidants ออกจาก neural mitochondrial และสีร้�าง superoxide anion ได�มาก• ปีร้�มาณของ A ntioxidant enzymes ใน extracellular space ม�น�อย:
- SOD ใน neurons- GSH และ GPX (peroxidases) ใน astrocytes- activity ของ Catalase และ - GSH Px ม�ต3$า
• Oxidative stress เก�ดข56นได�โดยหลายกลไก เช้%น - การ้เพ�$ม intracellular free Ca2+
- การ้หล�$ง excitatory amino acids (Glutamate)***
CNS และ Oxidative stress
- (GSH=glutathione;GSH Px=glutathione peroxidase)
Reactions important in the production anddefense from reactive species in neurons
O2 + e- O2-. H2O2 + O2
SOD
2H+
OH. + OH- + Fe3+
(Fenton Reaction)
Fe2+/Cu+
R. (organic radical)
RH (organic compound)
RO2
(peroxyradical)O2
ONOO-
NO2+
Nitration ofresiduetyrosine
O2
+ OH- + OH.
-(Haber Weissreaction)
.NO2 + OH.
H2O + O2
H2O + O2 - -GSH Px GSH Red
GSSG
GSH
Catalase
SOD
H2O2
NO.
Fe2+ + O2Fe3+
- GSH Px = glutathione peroxidase; SOD=super oxide dismutase;
GSSH = glutathione disulfide; ONOO-=peroxynitrite; GSH = glutathione; O
2
-. =superoxide species;- GSH red = glutathione reductase; OH. =hydroxyl species
XJunk Food
Anti-oxidantmenu
ล!กจ8า มาก�น antioxidants เพ9$อจะได�ลดการ้ที่3าลายเซิลล�สีมอง
ที่�$เก�ดจาก oxidants ใน junk food
GluNMDANMDAR1/NMDAR2A
high Mg2+ sensitivity
--mGluR II,III
(basal negative feedback)
+ -mGluR I
-mGluR I+
AMPA
Nitric oxide (NO) as-an intercellular messenger
-an atypical neurotransmitter
In neurotransmitterrelease
dd ddddddddddPAF-R
PAFHigh Ca2+
Long term potentiation(LTP)
Ca2+ mediated signals
- การ้เร้�ยนร้!� และความจ3า-neuroplasticity, etc.
Ca2+ NO
H2
O2
-enhanced NMDA dependent
LTP in hippocampus
Synaptic plasticity
2003(Kamsler & Segal, )
Functions of brain plasticit y
- Brain development- Learning & memory-Psychiatric disorders- Neurological disorders
H2O2, a membrane-permeable form of ROS,normally produced in living cells and synapses.
Hydrogen peroxide (H2O2)
AgingTraumaStroke
Parkinson’s disease (PD)Huntington’s disease (HD)
Alzheimer’s disease (AD) Amyotrophic lateral sclerosis (ALS)
Multiple sclerosis (MS)
Heart
Joints
LungMulti-organ
Vessels
GI
Eye Kidney Skin
OXIDATIVE STRESS
Brain
Degenerative retinal damageCataractogenesis
Renal graftGlomerulonephritis
Ischemic bowel Liver injury
VasospasmAtherosclerosis
AgingCancerDM
AsthmaHyperoxia
Rheumatoid arthritis
BurnDermatitisPsoriasis
Infarction
d dddddddd ( et al.,2003)
Aging, Trauma & Stroke
Na+-K+- pump failure
Membrane depolarization
Opening of voltage-sensitive Ca2+ channels
Elevation of intracellular Ca2+ levels
Glutamate release
Activation of NMDA,AMPA & metabotropic receptors
Stroke Reduction of blood flow (ischemia/hypoxia)
Depletion of energy stores
Activation of NOsynthase,lipases,
proteases andendonuclease
Apoptosis Irreversible cell damageCELL DEATH
Acidosis
Reperfusion
Inflammation
Release of cytokines
Failure of Ca2+
-buffering sys tems and pumps
AgingOther factors
NO production
Free-radicalformation
Lipid peroxidation
(Mandel et al., 2003)
Nitric oxide
d dddddd dddddddddd dddd
-Reduction in ubiquitinddddddddd d dddddd
Proteinaggregation
Neuronaldeath
Biochemical events associated with neurodegeneration of DAneurons in
PDddddddddd dddddddddddddd
ddddddddddd
Impaired cellularrespiration
Iron accumulation, oxidativestress & inflammation
Parkinson’s Disease
Alzheimer’s Disease
A generation
Oxidation -Excitotoxicity
A -aggregation
-Inflammation
-Tau hyperphosphorylation
Cognitive& behavioralabnormalities-Neurotransmitter
deficit,- Loss of neuroplasticity
Senile plaque with microglial activation
Neurofibrillarytangles
secretase secretase
Non amyloidogenicpathway
Amyloidogenicpathway secretase secretase
A
Celldeath
(Gamblin et al., 2000)
Reactive Oxygen Species
Amyotrophic Lateral Sclerosis
2000(Eisen, )
Free Radical Damage to Motor Neurons
Hydrogenperoxide
Oxygen radical
Environmental factors Genetic factors
ROSproduction
Macrophage
Excitotoxicity Transcription factors
Glutamate
Demyelination -Gene upregulation (I.e., TNF ) Axonal damage
Oligodendrocyte and neuronal loss
Sources of ROS & cellular events in MS
Multiple Sclerosis
- 200(Gilgun Sherki et al.,4)
Cellular Pathogenesis in HD
• Antioxidant vitamins• Plant polyphenols• Human endogenous ligands• Female sex hormone: Estrogen & Phytoestrogens
Antioxidant vitamins
Ascorbic acid (vit C)
-Alpha tocopheral
(vit E)Antioxidants Pro-oxidants
Neuroprotectants
• Both Vit C & E do not reduce risk of dementia
or PD( CNS Drugs 2 0 0 3 ;Cummings, N Engl J Med 2004)
• Vit E but not Vit C could have a role in ALS
prevention: clinical trials (Ascherio et al., Ann Neurol 2005)
• Potentiate extrapyramidal e ffects of haloperidol & NOS in
hi bi t or s (Lazzarini et al., Psychopharmac ol, 2005)
• -Vit C: Hb denaturation in G - 6 PD def. (Papandreou & Rakitzis, 19
9 0 )
• Vit E: antioxidative enzyme s in erythrocytes (Eder et al., 2002)
Vitamin A & beta-carotene
(Ono et al., Exp Neurol 2004)
dddd-dddddddd d dddddddd ddddd = > > .
Vitamins B2, B6, C, and E at50 and 100 μM
had no inhibitory effect
Antiamyloidogenic activity (in cell culture)
Electronmicrograph of fibril extension
Control: 0 h Control: 6 h +retinol: 6 h
- Ginkgo biloba (EGb)- Catechins- Caffeic acid phenethyl ester ( ’ )
Ginkgo biloba (EGb)แปีะก:วย
Free radical scavengersFlavonoids Egb had small but significant effect in AD patients
(Cummings, N Engl J Med 2004)
EGb= Gingko biloba extract 3 wks pretreatment
Control
10 g 6-OHDA ddd+50 /
100+ mg/kd dd d
150+ mg/kg EGd
(Ahmad et al., J Neurochem, 2 0 0 5 )
The expression of tyrosine hydroxylase (DA neuron) in
substantia nigra of rat (PD model)
•antioxidant•free radical scavenging•MAO-B inhibiting•DA-enhancing mechanisms
Rescue the DA neurons(PD model)
Catechins Camellia sinensis
A group of flavonoids; ~- 30 45% of
the solid green tea extract- - - - ( ) epigallocatechin 3 gallate (EGCG)
- - ( ) epigallocatechin (EGC)- - ( ) epicatechin (EC)
- - - - ( ) epicatechin 3 gallate (ECG)
~10%
EGCG: modulation of cell death genein Parkinson’s model
20(Mandel& Youdim, Free Rad Biol Med04) ddddddddd=
ddd ddd ddddddddd ddddddddddddddddddd ddddddddd
5 0 mg/kg EGCG i.p., after ischemia; 72rats were killed h post ischemia.
20(Rahman et al., Neurosci Lett05)
EGCG as an intervention of cerebral ischemia
Infa
rcS
ize
(mm3
)
Antioxidant prop.EGCG=ECG>EGC>EC
Caffeic acid phenethyl ester(CAPE)
-Active antioxidant flavonoids (4 5 5 5 %) from honeybee propolis
d ddddddd dddddddddd ddddd( )
dddddddddddd ddddd dddddd=
Control
6-OHDA
6-OHDA+ CAPE Effect of CAPE (dd
dd2+-ddddddd d dd-d ddddddddd ddd ddddd d ddddddddddd
dddd d ddddddd dddd d d2 0
05)
Propolis = neuroprotectant; a good candidate for in vivo models
ddd d dd dddd dddddddddd dddd dd: beneficially influence the course of EAE
in mice but, instead, suppress recovery ddddd dddddddddddd ddddddd.
- (flavonoids tested apigenin, luteolin, , , ,
fisetin & curcumin)
Biochemical Pharmacology 70 (2005) 220-228
Human endogenous ligands
1 0 ( )
=important antioxidant in bothmitochondria and lipid membrane
Slow down functional decline in PD patients (Frucht, CNS Drugs 2005)
Protect DA neuronal death from pesticide rotenone (Moon et al., J Neurochem 2005)
360mg/day: therapeutic effect in HD patients (Korozhetz et al., Ann Neurol 1997)
Coenzyme Q10 has the potential to be used as a therapeutic
intervention for neurodegenerativediseases.
(Somayajulu et al., Neurobiol Dis 2005)
- Lipoic acid (-LA)
A biological antioxidant , cofactor in many mitochondrial reactions
EAE= experimental autoimmune encephalomyelitis; a model
for MS
(Morini et al., J Neuroimmunol 2004)
-LA=a potential therapy for MS(mechanisms other than its
antioxidant activity)
Melatonin
- (Hardeland & Pandi Perumal, Nutr Met 2005)
Natural compound of almost ubiquitous occurrence
d ddddddddd=
Therapeutic trials with melatonin:
slowing the progression of AD but not of PD. (Srinivasan et al., Neurotox Res 2005)
(Ozdemir et al.,Neurosci Lett 2005)
CA1
CA3
DG
Melatonin protect hippocampus from the effect of traumatic Brain Injury
Female sex hormone: Estrogen & Phytoestrogens
(Amantea et al., Pharmacol Res, 2005)
Modulation ofgene
transcription
Inhibition ofcell death
Anti-inflammatoryactivity
d dddddddddddeffects
dddddddd ddddddddd( )
-dd-dd
ddddddddddd d dddneurotrophin
dddddd ddddddddddddpathways
-Rapid non genomicdddddddddddddresponses
Modulation ofneurotransmitter
systems
Neurotrophinreceptors
Membranebinding sites
Neurotransmitterreceptors
Antioxidanteffects
Estroge & Brain Plasticity Estrogen supplement
increase dendritic knobEstrogen
supplement Control
Rat’s brain: cognitive area
Estrogen Replacement Therapy:risk (uterine & breast cancer) VS benefit?
A brain selective estrogen receptor modulator
(NeuroSERM ) (Brinton, 2 0 0 4 )
- A non feminizing estrogen,- - - -2 1 4( adamantyl)
-methylestrone (ZYC 26) (Perez et al., 2 0 0 5 )
ERT
Phytoestrogens= natural SERMs
Pueraria mirifica (กวาวเคร้9อ ) :isoflavonoids
Soy isoflavones: Genistein, Daiazein,
Glycitein etc.
Caenorhabditis elegan s
(C. elegans)
Soy isoflavone glycitein protects against betaamyloid- induced toxicity and oxidative stress in transgenic
Caenorhabditis elegans. - 2005GutierrezZepedaetal.,BMC Neur osci
Glycitein
May have therapeutic potential for prevention of A associated
neurodegenerative disorders
Main results- No significant effect on the
primary outcome measure was - observed in a meta analysis of
antioxidants in general when combining the results.
- No significant differences were demonstrated in secondary
outcome measures
Author’s conclusion- While there is no substantial
clinical trial evidence to support their clinical use, there is no clear
contraindication.
The Cochrane Library 2005 3, Issue
Antioxidant treatment for ALS
Antioxidant treatment for HD
Antioxidant efficacy was not observed in human clinical trial. Studies have
-been planned for other free radical scavengers. (Gardian & Veesei, J Neural Trans 2004)
Antioxidants and neurology
Clinical evidence that antioxidants agents may prevent or slow the course of these
diseases is still relatively unsatisfactory, and unsufficient to strongly modify
the clinical practice. (Casetta et al., Curr Pharm Des. 2005)
Normal neurons Damaged neurons
Neuronal Cell Death
Oxidants & Neurodegenerative disorders
Free radicals cellular defence mechanism- enzymes: SOD, Catalase- others: vit.C, vit.E
Oxidative metabolism
-(PD) DA DOPACMAO-B
.OH + OH-
-Inflammation(MS)
Abnormal proteins- Alzheimer’s disease & amyloid- Prion protein & Prion disease (Mad cow)
Excitotoxicity (Trauma, Stroke, Aging)
Genetic defect:e.g. Mutation ofSOD1 & ALS
Oxidative stress
mismatch
Mitochondrial dysfunction & cell damage
Energy deprivation& Cell death
VDAC=Voltage dependent anion channel ANT=Adenosine nucleotide translocase PBR=Peripheral benzodiazepine receptor
CK=Creatinine kinase CyD=Cyclophilin D
EGCG polyphenols
( & , Free Rad Biol Med 2 0 0 4 ;
dddd d dddd. , 2004Biochem ))
Radical scavenging Iron chelation
Increasing antioxidant defense
Green Tea Polyphenols
d ddddddddd-dddddddd d d
PKC ANTVDAC
COMT
Apoptotic genes dfibrils
NEUROPROTECTION
sAPP
?
?
X
Suggested potential targets of EGCG
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