Oxidative Stress in Autism Woody McGinnis

1. Oxidative Stress in AutismWoody McGinnis

2. OutlineWhat is “oxidative stress”?Why was it suspected?What was found?Is it causal?

3. Irene (Vicky) Colquhoun 1920-2000

4. David Horrobin1939-2003

5. Bernard Rimland1928-2006

6. Oxidation is electron loss Wood burning Fruit browning Rancid oil Cellular damage

7. Oxidative Toxins Suboptimal nutrition Emotional stress Genes

8. Imbalance Oxidative stress is the state in which oxidants overwhelm the antioxidant defense. It results in excess physical damage and functional impairment.

9. Pollution Chemicals Heavy metals Insecticides Herbicides Halothane Chlorine MSG Aspartame Cu and Fe Food color Infections Allergies Stress Oxidative

10. Oxidative Superoxide O2 ˉ˙ Hydroxyl OH˙ Nitric oxide NO˙ Peroxynitrite ONOOˉ Singlet oxygen 1O2 Hydrogen peroxide H2O2

11. Nutritional profile Published: lower red-cell P5P, selenium, fatty acids; plasma zinc and serum carnitine By abstract: lower red-cell magnesium, zinc; plasma A, C, E, B3, B12 and folate

12. Oxidized biomolecules Lipids Proteins Sugars Nucleic acids

13. NO˙ and intestinal monolayers

14. Cells on fire

15. Menanedione Injury

16. Low energy Excitotoxicity Higher toxins Lower nutrients Lower endogenous defenses Cause AND effect of oxidative stress

17. Oxidative stress Low energy Excitotoxicity

18. Mercury blocks energy production Lead and tin over-excite via calcium influx Free radicals from unbound copper and iron Oxidative mechanisms

19. Endogenous defense Glutathione family: GSH, GSHPx, GST Metallothionein (MT) Superoxide dismutase (SOD) Catalase Melatonin Estrogen

20. Vitamin C Zinc Vitamin E Carnosine Vitamin A Carnitine B vitamins CoQ10 Selenium DHA Magnesium Vanilla Antioxidant nutrients

21. Constituent of SOD Blocks lipid peroxidation Shields -SH groups Induces and protects MT Maintains vitamin A level If low, ↑ intestinal NO˙ Zinc as antioxidant

25. B6 as antioxidant Protects gut GSHPx Protects brain GAD Mitochondrial Function Production of GSH

26. Marginal B6 deficiency Lowers GSHPx Lowers glutathione reductase Increases lipid peroxidation Promotes mitochondrial decay

27. Magnesium as antioxidant Blocks glutamate receptors Production of NADPH

28. Selenium as antioxidant Binds Hg and spares E Protects mitochondria Borderline deficiency reduces GSHPx

29. Gut is sensitive Microbes and food Glutathione import needs If low zinc, rapid MT depression Low ileal GSH and GST

30. Brain is sensitive High oxygen consumption Oxidizable catecholamines Fragile blood-brain barrier Modest catalase and GSH High glutamate, Fe and fat

31. Suggestive ↓ Nutrition ↑ Toxins ↓ Energy ↓ Endogenous protection Response to antioxidants Response to chelation

32. Peripheral phenotype More oxidants ↑NO˙(x2)* and XO (x3) Less protection ↓GSH, GSHPx*, catalase ceruloplasmin, transferrin More oxidized biomolecules ↑LPO (x2)* and isoprostanes

33. GSH in autism p = 0.0004

34. Suggestive • Elevated peripheral BDNF • Depressed cholinergic, GAD and ATP in brain • Hypoperfusion and ERG’s • Language loss correlates with protective enzymes • Response to antioxidants and hyperbaric

35. Oxidized brain ↑ Nitrotyrosine, correlates with mercury ↑ Axonal CEP, isolevuglandin and hemoxygenase ↑ Lipofuscin, associated with neuronal loss

36. Harvard study Increased cerebellar nitrotyrosine (3-NT) Cerebellar 3-NT and mercury correlated p = 0.0001

37. Case Western study • Parallel uptake of three oxidative biomarkers in all cerebrocortical and hippocampal samples • Staining primarily axonal • No such changes in controls

38. Carboxyethylpyrrole (CEP)

40. Univ. M. Hernandez Areas 22 (speech), 39 (reading), 44 (language production). Age 7- 44 years. Progressive ↓ neurons and ↑ glial cells in specific layers. Progressively ↑ lipofuscin throughout.

41. Lipofuscin facts Oxidized lipid and cross-linked protein. Depot for heavy metals. Classically associated with neurodegeneration. Inverse to brain activity and slowed by vitamin E.

43. Cells with lipofuscin

44. Vitamin E deficiency From malabsorption, poor transport, or subclinical coeliac disease. Lipofuscin is hallmark An early neurodegenerative disease clearly resulting from oxidative stress.

45. Vitamin E model Only signs at birth may be mild anemia and bilirubin elevation. Diarrhea in malabsorbers, then begin neurological signs (gait, weakness, eye movements) at 18-24 months. E-acetate may halt neurological decline

46. Oxidative stress as cause? It is accurate—and useful—to think of mechanisms or diseases as “cause”. Parallels to vitamin E. Pre- and peri-natal findings: maternal stress, birth complications, BDNF.

47. Oxidative stress as cause? Maternal stress modulates effect of neurotoxicants. Stress-hormone administration during gestation→persistent post-natal susceptibility to environmental oxidants. Polymorphisms: GST, COMT, etc.

48. Oxidative stress as cause? Prominent oxidative mechanisms of toxicity for the diverse family of recognized triggers: thalidomide, valproate, vaccines. Dual manifestations of oxidative stress: physical modifications plus reversible redox-dependent functions.

49. Oxidative stress as cause? Diverse therapies are anti-oxidant; aggravants often pro-oxidant. IBR study: experimental oxidative stress reduces neuronal stem-cell proliferation and organization.

50. NOSS Neurodevelopmental Oxidative Stress Syndrome