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Illness suggested to be associated with oxidative stress Eye Brain Chest Lower abdomen Abdomen Body Air tube Face.

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Presentation on theme: "Illness suggested to be associated with oxidative stress Eye Brain Chest Lower abdomen Abdomen Body Air tube Face."— Presentation transcript:

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2 Illness suggested to be associated with oxidative stress Eye Brain Chest Lower abdomen Abdomen Body Air tube Face

3 Radiation UV radiation Smoking Air pollutants Agricultural chemicals Additives Detergents Activated oxygen Free radicals Antioxidants Vitamin E Vitamin C  -Carotene Flavonoids Ubiquinone Scavenging

4 ORAC=Oxygen Radical Absorbance Capacity Blackcurrant Strawberry Raspberry

5 “Antioxidants! Antioxidants!….”

6 Women Men ( ปี ค. ศ.) Year % ร้อยละของการเกิดผลเสีย จากการใช้ผลิตภัณฑ์ฯ การใช้ผลิตภัณฑ์เสริมอาหารของผู้สูงอายุที่ร่วมในกลุ่ม the New Mexico Aging Process Study Wold et al., J Am Diet Assoc, 2005;105:54-63.

7 1.Generation of free radicals, oxidative stress & their’s damaging effects: ศ. ดร. ไมตรี สุทธจิตต์ 4.Antioxidants in cosmetics: รศ. ดร. พรรณวิภา กฤษฏาพงศ์ 3.Antioxidants in neurodegenerative disorders: รศ. ดร. จินตนา สัตยาศัย 2.Antioxidants in metabolic disorders: รศ. ดร. วีรพล คู่คงวิริยพันธ์

8 รศ. ดร. จินตนา สัตยาศัย ภาควิชาเภสัชวิทยา คณะแพทยศาสตร์มหาวิทยาลัยขอนแก่น

9 สมองมีปริมาณไขมันไม่อิ่มตัว (PUFAs) เป็นจำนวนมากทำให้ไว ต่อภาวะเครียดทางออกซิเดชัน สมองใช้ออกซิเจนในอัตราที่สูงมาก จึงมีการปล่อย oxidants ออกจาก neural mitochondrial และสร้าง superoxide anion ได้มาก ปริมาณของ Antioxidant enzymes ใน extracellular space มีน้อย : -SOD ใน neurons -GSH และ GPX (peroxidases) ใน astrocytes -activity ของ Catalase และ GSH-Px มีต่ำ Oxidative stress เกิดขึ้นได้โดยหลายกลไก เช่น - การเพิ่ม intracellular free Ca 2+ - การหลั่ง excitatory amino acids (Glutamate)*** CNS และ Oxidative stress (GSH=glutathione;GSH-Px=glutathione peroxidase)

10 Reactions important in the production and defense from reactive species in neurons O 2 + e - O 2 -. H 2 O 2 + O 2 SOD 2H + OH. + OH - + Fe 3+ (Fenton Reaction) Fe 2+ /Cu + R. (organic radical) RH (organic compound) RO 2 (peroxy radical) O2O2 ONOO - NO 2 + Nitration of residue tyrosine O 2 + OH - + OH. (Haber-Weiss reaction). NO 2 + OH. H 2 O + O 2 GSH-Px GSH-Red GSSG GSH Catalase SOD H2O2H2O2 NO. Fe 2+ + O 2 Fe 3+ 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

11 X Junk Food Anti- oxidant menu ลูกจ๋า มากิน antioxidants เพื่อ จะได้ลดการทำลายเซลล์สมอง ที่เกิดจาก oxidants ใน junk food

12 Glu NMDA NMDAR1/NMDAR2A high Mg 2+ sensitivity - mGluR-II,III (basal negative feedback) + mGluR-I + AMPA Nitric oxide (NO) as -an intercellular messenger -an atypical neurotransmitter In neurotransmitter release As neurotoxin PAF-R PAF High Ca 2+ Long term potentiation (LTP) Ca 2+ mediated signals - การเรียนรู้ และความจำ -neuroplasticity, etc. Ca 2+ NO

13 H 2 O 2 enhanced NMDA-dependent LTP in hippocampus Synaptic plasticity (Kamsler & Segal, 2003) Functions of brain plasticity -Brain development -Learning & memory -Psychiatric disorders -Neurological disorders H 2 O 2, a membrane-permeable form of ROS, normally produced in living cells and synapses. Hydrogen peroxide (H 2 O 2 )

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15 Aging Trauma Stroke Parkinson’s disease (PD) Huntington’s disease (HD) Alzheimer’s disease (AD) Amyotrophic lateral sclerosis (ALS) Multiple sclerosis (MS) Heart Joints Lung Multi-organ Vessels GI EyeKidney Skin OXIDATIVE STRESS Brain Degenerative retinal damage Cataractogenesis Renal graft Glomerulonephritis Ischemic bowel Liver injury Vasospasm Atherosclerosis Aging Cancer DM Asthma Hyperoxia Rheumatoid arthritis Burn Dermatitis Psoriasis Infarction

16 (From Calabresi et al.,2003) Aging, Trauma & Stroke Na + -K + -pump failure Membrane depolarization Opening of voltage- sensitive Ca 2+ channels Elevation of intracellular Ca 2+ levels Glutamate release Activation of NMDA,AMPA & metabotropic receptors Stroke Reduction of blood flow (ischemia/hypoxia) Depletion of energy stores Activation of NO synthase,lipases, proteases and endonuclease Apoptosis Irreversible cell damage CELL DEATH Acidosis Reperfusion Inflammation Release of cytokines Failure of Ca 2+ buffering sys- tems and pumps Aging Other factors NO production Free-radical formation Lipid peroxidation

17 (Mandel et al., 2003) Nitric oxide Release of ferritin iron Reduction in ubiquitin- proteosome system Protein aggregation Neuronal death Biochemical events associated with neurodegeneration of DAneurons in PD Glutamate excitotoxicity neurotoxins Impaired cellular respiration Iron accumulation, oxidative stress & inflammation Parkinson’s Disease

18 Alzheimer’s Disease A  generation Oxidation Excito- toxicity A  aggre- gation Inflam- mation Tau hyper- phosphorylation Cognitive & behavioral abnormalities -Neurotransmitter deficit, -Loss of neuroplasticity Senile plaque with microglial activation Neurofibrillary tangles  secretase  secretase Non amyloidogenic pathway Amyloidogenic pathway  secretase AA Cell death (Gamblin et al., 2000) Reactive Oxygen Species

19 Amyotrophic Lateral Sclerosis (Eisen, 2000) Free Radical Damage to Motor Neurons Hydrogen peroxide Oxygen radical

20 Environmental factorsGenetic factors ROS production Macrophage Excitotoxicity Transcription factors Glutamate DemyelinationGene upregulation (I.e., TNF-  )Axonal damage Oligodendrocyte and neuronal loss Sources of ROS & cellular events in MS Multiple Sclerosis (Gilgun-Sherki et al., 2004)

21 Cellular Pathogenesis in HD

22 Antioxidant vitamins Plant polyphenols Human endogenous ligands Female sex hormone: Estrogen & Phytoestrogens

23 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 2003;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 effects 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)

24 Vitamin A & beta-carotene (Ono et al., Exp Neurol 2004) retinol = retinal > beta-carotene > retinoic acid. Vitamins B2, B6, C, and E at 50 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

25 -Ginkgo biloba (EGb) -Catechins -Caffeic acid phenethyl ester (from honeybee’s propolis)

26 Ginkgo biloba (EGb) แปะก๊วย Free radical scavengers Flavonoids 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 +50 mg/kg EGb +100 mg/kg EGb +150 mg/kg EGb (Ahmad et al., J Neurochem, 2005) 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)

27 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 gene in Parkinson’s model (Mandel& Youdim, Free Rad Biol Med 2004) EGCG=potential candidate for the treatment of neurodegenerative disorders 50mg/kg EGCG i.p., after ischemia; rats were killed 72h post ischemia. (Rahman et al., Neurosci Lett 2005) EGCG as an intervention of cerebral ischemia Infarc Size (mm 3 ) Antioxidant prop. EGCG=ECG>EGC>EC

28 Caffeic acid phenethyl ester (CAPE) Active antioxidant flavonoids (45-55%) from honeybee propolis Cultured cerebellar granule neurons (CGN) red fluorescent=death neuron Control 6-OHDA + CAPE Effect of CAPE (  on Ca 2+ -induced Cyt-C release in rat liver mitochondria (Noelker et al., Neurosci Lett 2005) Propolis = neuroprotectant; a good candidate for in vivo models

29 Model for MS: oral flavonoids fail to beneficially influence the course of EAE in mice but, instead, suppress recovery from acute inflammatory damage. (flavonoids tested-apigenin, luteolin, quercetin, hesperitin, morin, fisetin & curcumin) Biochemical Pharmacology 70 (2005)

30 Human endogenous ligands Coenzyme Q10 (ubiquinone) =important antioxidant in both mitochondria 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)

31 Coenzyme Q10 has the potential to be used as a therapeutic intervention for neurodegenerative diseases. (Somayajulu et al., Neurobiol Dis 2005)

32  -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)

33 Melatonin (Hardeland & Pandi-Perumal, Nutr Met 2005) Natural compound of almost ubiquitous occurrence AMK=Melatonin metabolite

34 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

35 Female sex hormone: Estrogen & Phytoestrogens (Amantea et al., Pharmacol Res, 2005) Modulation of gene transcription Inhibition of cell death Anti-inflammatory activity Neurotrophic effects Estrogen receptors (intracellular) -ER  -ER  Interaction with neurotrophin signal transduction pathways Rapid non-genomic intracellular responses Modulation of neurotransmitter systems Neurotrophin receptors Membrane binding sites Neurotransmitter receptors Antioxidant effects

36 Estroge & Brain Plasticity Estrogen supplement increase dendritic knob Estrogen supplement Control Rat’s brain: cognitive area Estrogen Replacement Therapy: risk (uterine & breast cancer) VS benefit? A brain selective estrogen receptor modulator (NeuroSERM ) (Brinton, 2004) A non-feminizing estrogen, 2-(1-adamantyl)-4- methylestrone (ZYC-26) (Perez et al., 2005) ERT Phytoestrogens= natural SERMs

37 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 potential for prevention of A  associated neurodegenerative disorders

38 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, Issue 3 Antioxidant treatment for ALS

39 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)

40 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)

41 Normal neuronsDamaged neurons Neuronal Cell Death

42 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 &  amyloid -Prion protein & Prion disease (Mad cow) Excitotoxicity (Trauma, Stroke, Aging) Genetic defect: e.g. Mutation of SOD1 & ALS Oxidative stress mismatch Mitochondrial dysfunction & cell damage Energy deprivation & Cell death

43 VDAC=Voltage dependent anion channel ANT=Adenosine nucleotide translocase PBR=Peripheral benzodiazepine receptor CK=Creatinine kinase CyD=Cyclophilin D EGCG polyphenols (Mandel & Youdim, Free Rad Biol Med 2004; Weinreb et al., J Nutr Biochem 2004)) Radical scavenging Iron chelation Increasing antioxidant defense Green Tea Polyphenols Neurotoxin-induced ROS PKCANT VDAC COMT Apoptotic genes A  fibrils NEUROPROTECTION sAPP  ? ? X Suggested potential targets of EGCG


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