Oxidative Stress in Autism Woody McGinnis
description
Transcript of Oxidative Stress in Autism Woody McGinnis
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 O2 ˉ˙
Hydroxyl OH˙
Nitric oxide NO˙
Peroxynitrite ONOOˉ
Singlet oxygen 1O2
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 Zinc
Vitamin E Carnosine
Vitamin A Carnitine
B vitamins CoQ10
Selenium DHA
Magnesium 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
Plasma Total GSH
Control Autism2
3
4
5Control
Autism
PBMC Total GSH
Control Autism0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5Control
Autism
Plasma Total Cysteine
Control Autism0
100
200
300Control
Autism
PBMC Total Cysteine
Control Autism0.0
0.1
0.2
0.3
0.4
0.5
0.6Control
Autism
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.
From malabsorption, poor transport, or subclinical coeliac disease.
Lipofuscin is hallmark
An early neurodegenerative disease clearly resulting from oxidative stress.
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 redox-
dependent functions.
Diverse therapies are anti-oxidant; aggravants often pro-oxidant.
IBR study: experimental oxidative stress reduces neuronal stem-cell proliferation
and organization.