illness suggested to be associated with oxidative stress · oxidative metabolism-(pd) da dopac...
TRANSCRIPT
Illn
ess
sugg
este
d to
be
asso
ciat
edwi
th oxi
dative
str
ess
Eye Brain
Chest
Lower abdomen
Abdomen
Body
Air tubeFace
RadiationUV radiation
Smoking
Air pollutants
Agriculturalchemicals
Additives
DetergentsActivated oxygen
Free radicals
AntioxidantsVitamin EVitamin Cβ-Carotene
FlavonoidsUbiquinone
Scavenging
http://www.hsrmagazine.com/articles/2c1specialty2.htmlORAC=Oxygen Radical Absorbance Capacity
Blackcurrant
Strawberry
Raspberry
“Antioxidants! Antioxidants!….”
WomenMen
50
40
30
20
10
01994 1995 1996 1997 1998 1999 (ป ค.ศ.)
42.1845.62
41.16
27.9726.77
20.920.0820.09
18.7116.06
14.42
11.72
Year 1994 1995 1996 1997 1998 1999
% 11.9 19.7 13.2 24.1 29.3 30.6
รอยละของการเกิดผลเสียจากการใชผลิตภัณฑฯ
การใชผลิตภัณฑเสริมอาหารของผูสูงอายุที่รวมในกลุมthe New Mexico Aging Process Study
Wold et al.,J Am Diet Assoc, 2005;105:54-63.
1.Generation of free radicals, oxidative stress& their’s damaging effects: ศ.ดร.ไมตรี สุทธจิตต
4.Antioxidants in cosmetics:รศ.ดร.พรรณวิภา กฤษฏาพงศ
3.Antioxidants in neurodegenerativedisorders: รศ.ดร.จินตนา สัตยาศัย
2.Antioxidants in metabolicdisorders: รศ.ดร.วีรพล คูคงวิริยพันธ
รศ.ดร. จินตนา สัตยาศัยภาควิชาเภสัชวิทยาคณะแพทยศาสตรมหาวิทยาลัยขอนแกน
•สมองมีปริมาณไขมันไมอิ่มตัว (PUFAs) เปนจํานวนมากทําใหไวตอภาวะเครียดทางออกซิเดชัน
•สมองใชออกซิเจนในอตัราที่สูงมาก จึงมีการปลอย oxidants ออกจาก neural mitochondrial และสราง superoxide anion ไดมาก •ปริมาณของ Antioxidant enzymes ใน extracellular space มีนอย:
-SOD ใน neurons-GSH และ GPX (peroxidases) ใน astrocytes-activity ของ Catalase และ GSH-Px มีต่ํา
•Oxidative stress เกดิขึ้นไดโดยหลายกลไก เชน-การเพิ่ม intracellular free Ca2+
-การหลั่ง 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 (peroxy radical)O2
ONOO-
NO2+
Nitration ofresiduetyrosine
O2 + OH- + OH.
(Haber-Weissreaction)
.NO2 + OH.
H2O + O2H2O + O2
GSH-Px GSH-RedGSSG
GSH
Catalase
SOD
H2O2
NO.
Fe2+ + O2
Fe3+
GSH-Px = glutathione peroxidase; SOD=super oxide dismutase;GSSH = glutathione disulfide; ONOO-=peroxynitrite;GSH = glutathione; O2
-.=superoxide species;GSH-red = glutathione reductase; OH.=hydroxyl species
Junk Food
Anti-oxidantmenu
ลูกจา มากิน antioxidants เพื่อจะไดลดการทําลายเซลลสมองที่เกิดจาก oxidants ใน junk food
GluNMDANMDAR1/NMDAR2Ahigh 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
As neurotoxinPAF-R
PAFHigh Ca2+
Long term potentiation(LTP)
Ca2+ mediated signals
-การเรยีนรู และความจํา-neuroplasticity, etc.
Ca2+ NO
H2O2 enhanced NMDA-dependentLTP in hippocampus
Synaptic plasticity
(Kamsler & Segal, 2003)
Functions of brain plasticity -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)
Aging TraumaStrokeParkinson’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 bowelLiver injury
VasospasmAtherosclerosis
AgingCancerDM
AsthmaHyperoxia
Rheumatoid arthritis
BurnDermatitisPsoriasis
Infarction
(From Calabresi 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
StrokeReduction 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
Release offerritin iron
Reduction in ubiquitin-proteosome system
Proteinaggregation
Neuronaldeath
Biochemical events associated withneurodegeneration of DAneurons in PD
Glutamate excitotoxicity
neurotoxins
Impaired cellularrespiration
Iron accumulation, oxidativestress & inflammation
Parkinson’s Disease
Alzheimer’s Disease
Aβ generation
Oxidation Excito-toxicity
Aβ aggre-gation
Inflam-mation
Tau hyper-phosphorylation
Cognitive& behavioralabnormalities-Neurotransmitter
deficit,-Loss ofneuroplasticity
Senile plaque withmicroglial activation
Neurofibrillarytangles
β secretase α secretase
Non amyloidogenicpathway
Amyloidogenicpathway γ secretase γ secretase
Aβ
Celldeath
(Gamblin et al., 2000)
Reactive Oxygen Species
Amyotrophic Lateral Sclerosis
(Eisen, 2000)
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-α) Axonal damage
Oligodendrocyte and neuronal loss
Sources of ROS & cellular events in MS
Multiple Sclerosis
(Gilgun-Sherki et al., 2004)
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-oxidantsNeuroprotectants
•Both Vit C & E do notreduce risk of dementiaor PD(CNS Drugs 2003;Cummings,N Engl J Med 2004)
•Vit E but not Vit Ccould have a role in ALSprevention: clinical trials(Ascherio et al., Ann Neurol 2005)
•Potentiate extrapyramidaleffects of haloperidol & NOS inhibitors (Lazzarini et al., Psychopharmacol,2005)
•Vit C: Hb denaturation in G-6-PD def. (Papandreou & Rakitzis, 1990)
•Vit E: antioxidative enzymes in erythrocytes (Eder et al., 2002)
Vitamin A & beta-carotene
(Ono et al., Exp Neurol 2004)
retinol = retinal > beta-carotene > retinoic acid.
Vitamins B2, B6, C, and E at50 and 100 µM
had no inhibitory effect
Antiamyloidogenic activity(in cell culture)
Electronmicrographof fibril extension
Control: 0 h Control: 6 h +retinol: 6 h
-Ginkgo biloba (EGb)-Catechins -Caffeic acid phenethyl ester
(from honeybee’s propolis)
Ginkgo biloba (EGb)แปะกวย
Free radical scavengersFlavonoidsEgb had small but significant effect in AD patients
(Cummings, N Engl J Med 2004)
EGb=Gingko biloba extract3 wks pretreatment
Control
10 µg 6-OHDA +50 mg/kg EGb
+100 mg/kg EGb +150 mg/kg EGb
(Ahmad et al., J Neurochem, 2005)
The expression of tyrosinehydroxylase (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)
CatechinsCamellia sinensis
A group of flavonoids; ~30-45% ofthe 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
(Mandel& Youdim, Free Rad Biol Med 2004)
EGCG=potential candidatefor the treatment of
neurodegenerative disorders50mg/kg EGCG i.p., after ischemia;rats were killed 72h post ischemia.
(Rahman et al., Neurosci Lett 2005)
EGCG as an interventionof cerebral ischemia
Infa
rc S
ize
(mm
3 )
Antioxidant prop.EGCG=ECG>EGC>EC
Caffeic acid phenethyl ester(CAPE)
Active antioxidant flavonoids (45-55%)from honeybee propolis
Cultured cerebellargranule neurons (CGN)
red fluorescent=death neuron
Control
6-OHDA
6-OHDA+ CAPE Effect of CAPE (µΜ) on
Ca2+-induced Cyt-C releasein rat liver mitochondria
(Noelker et al., Neurosci Lett 2005)
Propolis = neuroprotectant; a goodcandidate for in vivo models
Model for MS: oral flavonoids fail tobeneficially influence the course of EAEin mice but, instead, suppress recovery
from acute inflammatory damage.(flavonoids tested-apigenin, luteolin,
quercetin, hesperitin, morin,fisetin & curcumin)
Biochemical Pharmacology 70 (2005) 220-228
Human endogenous ligands
Coenzyme Q10 (ubiquinone)
=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 potentialto be used as a therapeutic
intervention for neurodegenerativediseases.
(Somayajulu et al., Neurobiol Dis 2005)
α-Lipoic acid (α-LA)A biological antioxidant , cofactor in many
mitochondrial reactions
EAE= experimental autoimmuneencephalomyelitis; a model
for MS
(Morini et al., J Neuroimmunol 2004)
α-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
AMK=Melatonin metabolite
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 theeffect of traumatic Brain Injury
Female sex hormone: Estrogen& Phytoestrogens
(Amantea et al., Pharmacol Res, 2005)
Modulation ofgene
transcription
Inhibition ofcell death
Anti-inflammatoryactivity
Neurotrophiceffects
Estrogen receptors(intracellular)
-ERα-ERβ
Interaction withneurotrophin
signal transductionpathways
Rapid non-genomicintracellularresponses
Modulation ofneurotransmitter
systems
Neurotrophinreceptors
Membranebinding sites
Neurotransmitterreceptors
Antioxidanteffects
Estroge & Brain PlasticityEstrogen supplement
increase dendritic knobEstrogen
supplement Control
Rat’s brain: cognitive area
Estrogen Replacement Therapy:risk (uterine & breast cancer) VS benefit?
A brain selective estrogenreceptor modulator
(NeuroSERM) (Brinton, 2004)
A non-feminizing estrogen,2-(1-adamantyl)-4-
methylestrone (ZYC-26)(Perez et al., 2005)
ERT
Phytoestrogens=natural SERMs
Pueraria mirifica (กวาวเครือ) :isoflavonoids
Soy isoflavones:Genistein, Daiazein,Glycitein etc.
Caenorhabditis elegans (C. elegans)
Soy isoflavone glycitein protects against betaamyloid-induced toxicity and oxidative stress in transgenic
Caenorhabditis elegans. Gutierrez-Zepeda et al., BMC Neurosci 2005
Glycitein
May have therapeutic potentialfor prevention of Aβ associatedneurodegenerative disorders
Main results-No significant effect on theprimary outcome measure wasobserved in a meta-analysis ofantioxidants in general whencombining the results.-No significant differenceswere demonstrated in secondaryoutcome measures
Author’s conclusion-While there is no substantialclinical trial evidence to supporttheir clinical use, there is no clearcontraindication.
The Cochrane Library2005, Issue 3
Antioxidant treatment for ALS
Antioxidant treatment for HDAntioxidant efficacy was not observed
in human clinical trial. Studies havebeen planned for other free-radicalscavengers. (Gardian & Veesei, J Neural Trans 2004)
Antioxidants and neurology
Clinical evidence that antioxidants agentsmay prevent or slow the course of thesediseases is still relatively unsatisfactory,
and unsufficient to strongly modifythe 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 DOPAC
MAO-B
.OH + OH-
-Inflammation(MS)
Abnormal proteins-Alzheimer’s disease & β 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 channelANT=Adenosine nucleotide translocasePBR=Peripheral benzodiazepine receptorCK=Creatinine kinaseCyD=Cyclophilin D
EGCG polyphenols
(Mandel & Youdim,Free Rad Biol Med 2004;Weinreb et al., J NutrBiochem 2004))
Radical scavengingIron chelation
Increasing antioxidant defense
Green Tea Polyphenols
Neurotoxin-inducedROS
PKC ANTVDAC
COMT
Apoptotic genes Aβ fibrils
NEUROPROTECTION
sAPPα
?
?
X
Suggested potential targets of EGCG