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 MSG
Chemicals Aspartame
Heavy metals Cu and Fe
Food color
Insecticides
Infections
Herbicides
Allergies
Halothane Stress
Chlorine
Superoxide O2 ˉ˙
Hydroxyl OH˙
Nitric oxide NO˙
Peroxynitrite ONOOˉ
Singlet oxygen 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 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
 P la s m a T o ta l G S H P B M C T o ta l G S H
5 3 .5
C o n tro l C o n tr o
A u tis m 3 .0
A u t is m
4 2 .5
2 .0
1 .5
3
1 .0
0 .5
2 0 .0
C o n tro l A u tis m 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 redox-
dependent functions.
 Diverse therapies are anti-oxidant;
aggravants often pro-oxidant.
IBR study: experimental oxidative stress
reduces neuronal stem-cell proliferation
and organization.