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Air pollutants

Agriculturalchemicals

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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

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- 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

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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