Oxidative Stress in Autism Woody McGinnis. Outline What is “oxidative stress”? Why was it suspected? What was found? Is it causal?

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.