Autism: “Neurodevelopmental Oxidative Stress Syndrome”?
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Oxidative Stress in Autism
Woody McGinnis
Outline
What is “oxidative stress”? Why was it suspected? What was found? Is it causal?
Irene (Vicky) Colquhoun
1920-2000
David Horrobin
1939-2003
Bernard Rimland
1928-2006
Wood burning Fruit browning Rancid oil Cellular damage
Toxins Suboptimal nutrition Emotional stress Genes
Oxidative stress is the state in which oxidants overwhelm the antioxidant defense. It results in excess physical damage and functional impairment.
Pollution Chemicals Heavy metals Insecticides Herbicides Halothane Chlorine
MSG Aspartame Cu and Fe Food color Infections Allergies Stress
Superoxide Hydroxyl Nitric oxide Peroxynitrite Singlet oxygen
O2 ˉ˙ OH˙ NO˙ ONOOˉ 1 O2
Hydrogen peroxide H2O2
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
Lipids Proteins Sugars Nucleic acids
Low energy Excitotoxicity Higher toxins Lower nutrients Lower endogenous defenses
Mercury blocks energy production Lead and tin over-excite via calcium influx Free radicals from unbound copper and iron
Glutathione family: GSH, GSHPx, GST Metallothionein (MT) Superoxide dismutase (SOD) Catalase Melatonin Estrogen
Vitamin C Vitamin E Vitamin A B vitamins Selenium Magnesium
Zinc Carnosine Carnitine CoQ10 DHA Vanilla
Constituent of SOD Blocks lipid peroxidation Shields -SH groups Induces and protects MT Maintains vitamin A level If low, ↑ intestinal NO˙
Microbes and food Glutathione import needs If low zinc, rapid MT depression Low ileal GSH and GST
High oxygen consumption Oxidizable catecholamines Fragile blood-brain barrier Modest catalase and GSH High glutamate, Fe and fat
↓ Nutrition ↑ Toxins ↓ Energy ↓ Endogenous protection Response to antioxidants Response to chelation
More oxidants ↑NO˙(x2)* and XO (x3) Less protection ↓GSH, GSHPx*, catalase ceruloplasmin, transferrin More oxidized biomolecules ↑LPO (x2)* and isoprostanes
P la s m a T o ta l G S H
5
P B M C T o ta l G S H
3 .5 3 .0 2 .5 2 .0
C o n tro l A u tis m
C o n tr o A u t is m
4
3
1 .5 1 .0 0 .5
2
C o n tro l
A u tis m
0 .0
C o n tr o l A u tis m p = 0.0004
• 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
↑ Nitrotyrosine, correlates with mercury ↑ Axonal CEP, isolevuglandin and hemoxygenase ↑ Lipofuscin, associated with neuronal loss
Increased cerebellar nitrotyrosine (3-NT) Cerebellar 3-NT and mercury correlated p = 0.0001
• Parallel uptake of three oxidative biomarkers in all cerebrocortical and hippocampal samples • Staining primarily axonal • No such changes in controls
Areas 22 (speech), 39 (reading), 44 (language production). Age 7- 44 years. Progressive ↓ neurons and ↑ glial cells in specific layers. Progressively ↑ lipofuscin throughout.
Oxidized lipid and cross-linked protein. Depot for heavy metals. Classically associated with neurodegeneration. Inverse to brain activity and slowed by vitamin E.
An early neurodegenerative disease clearly resulting from oxidative stress.
From malabsorption, poor transport, or subclinical coeliac disease. Lipofuscin is hallmark
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
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.
Maternal stress modulates effect of neurotoxicants. Stress-hormone administration during gestation→persistent post-natal susceptibility to environmental oxidants. Polymorphisms: GST, COMT, etc.
Prominent oxidative mechanisms of toxicity for the diverse family of recognized triggers: thalidomide, valproate, vaccines. Dual manifestations of oxidative stress: physical modifications plus reversible redoxdependent functions.
Diverse therapies are anti-oxidant; aggravants often pro-oxidant. IBR study: experimental oxidative stress reduces neuronal stem-cell proliferation and organization.
Oxidative Stress in Autism
Woody McGinnis
Outline
What is “oxidative stress”? Why was it suspected? What was found? Is it causal?
Irene (Vicky) Colquhoun
1920-2000
David Horrobin
1939-2003
Bernard Rimland
1928-2006
Wood burning Fruit browning Rancid oil Cellular damage
Toxins Suboptimal nutrition Emotional stress Genes
Oxidative stress is the state in which oxidants overwhelm the antioxidant defense. It results in excess physical damage and functional impairment.
Pollution Chemicals Heavy metals Insecticides Herbicides Halothane Chlorine
MSG Aspartame Cu and Fe Food color Infections Allergies Stress
Superoxide Hydroxyl Nitric oxide Peroxynitrite Singlet oxygen
O2 ˉ˙ OH˙ NO˙ ONOOˉ 1 O2
Hydrogen peroxide H2O2
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
Lipids Proteins Sugars Nucleic acids
Low energy Excitotoxicity Higher toxins Lower nutrients Lower endogenous defenses
Mercury blocks energy production Lead and tin over-excite via calcium influx Free radicals from unbound copper and iron
Glutathione family: GSH, GSHPx, GST Metallothionein (MT) Superoxide dismutase (SOD) Catalase Melatonin Estrogen
Vitamin C Vitamin E Vitamin A B vitamins Selenium Magnesium
Zinc Carnosine Carnitine CoQ10 DHA Vanilla
Constituent of SOD Blocks lipid peroxidation Shields -SH groups Induces and protects MT Maintains vitamin A level If low, ↑ intestinal NO˙
Microbes and food Glutathione import needs If low zinc, rapid MT depression Low ileal GSH and GST
High oxygen consumption Oxidizable catecholamines Fragile blood-brain barrier Modest catalase and GSH High glutamate, Fe and fat
↓ Nutrition ↑ Toxins ↓ Energy ↓ Endogenous protection Response to antioxidants Response to chelation
More oxidants ↑NO˙(x2)* and XO (x3) Less protection ↓GSH, GSHPx*, catalase ceruloplasmin, transferrin More oxidized biomolecules ↑LPO (x2)* and isoprostanes
P la s m a T o ta l G S H
5
P B M C T o ta l G S H
3 .5 3 .0 2 .5 2 .0
C o n tro l A u tis m
C o n tr o A u t is m
4
3
1 .5 1 .0 0 .5
2
C o n tro l
A u tis m
0 .0
C o n tr o l A u tis m p = 0.0004
• 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
↑ Nitrotyrosine, correlates with mercury ↑ Axonal CEP, isolevuglandin and hemoxygenase ↑ Lipofuscin, associated with neuronal loss
Increased cerebellar nitrotyrosine (3-NT) Cerebellar 3-NT and mercury correlated p = 0.0001
• Parallel uptake of three oxidative biomarkers in all cerebrocortical and hippocampal samples • Staining primarily axonal • No such changes in controls
Areas 22 (speech), 39 (reading), 44 (language production). Age 7- 44 years. Progressive ↓ neurons and ↑ glial cells in specific layers. Progressively ↑ lipofuscin throughout.
Oxidized lipid and cross-linked protein. Depot for heavy metals. Classically associated with neurodegeneration. Inverse to brain activity and slowed by vitamin E.
An early neurodegenerative disease clearly resulting from oxidative stress.
From malabsorption, poor transport, or subclinical coeliac disease. Lipofuscin is hallmark
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
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.
Maternal stress modulates effect of neurotoxicants. Stress-hormone administration during gestation→persistent post-natal susceptibility to environmental oxidants. Polymorphisms: GST, COMT, etc.
Prominent oxidative mechanisms of toxicity for the diverse family of recognized triggers: thalidomide, valproate, vaccines. Dual manifestations of oxidative stress: physical modifications plus reversible redoxdependent functions.
Diverse therapies are anti-oxidant; aggravants often pro-oxidant. IBR study: experimental oxidative stress reduces neuronal stem-cell proliferation and organization.
