Oxidative Stress in Autism Spectrum Disorders

by Woody McGinnis and Patricia Lemer

The word "stress" has many different meanings. Various factors, including birth trauma, ear infections and antibiotics can increase a cell’s susceptibility to stress. (See New Developments, 1:3, "Total Load Theory") Stress occurs at a cellular level through a chemical process called oxidation. Most cells in the body are vulnerable to oxidation. Cells in the gut and the brain, both abnormal in autism, are particularly sensitive. One reason could be that they are under too much stress from oxidation.

What is Oxidative Stress?

"Oxidative stress" occurs when the compounds which cause oxidation, "oxidants," overwhelm the body‘s natural defenses. Oxidants either enter the body as toxins from the environment or are by-products of the body’s normal metabolism. The body fights off oxidants with compounds called "antioxidants," which include vitamins and minerals from food and special enzymes which the body makes. When health is good, anti-oxidants outnumber oxidants. When oxidants prevail, cells suffer oxidative stress.

One important class of oxidants is "free radicals," which structurally have an unpaired electron, making them unstable and reactive, and allow them to act as oxidants. Not all oxidants are free radicals, but free radicals are major contributors to oxidative stress.

What Causes Oxidative Stress?

Research points to several conditions which suggest why children with autism are more likely to have oxidative stress:

• Low levels of anti-oxidant compounds, including vitamins A, C, and E, as well as selenium, zinc, magnesium, glutathione, glutathione peroxidase, and superoxide dismutase. When levels of these compounds are low, oxidants are freer to damage cells. Double-blind placebo-controlled studies have shown that either vitamin C or the anti- oxidant nutrient carnosine significantly improves behavior in children with autism.
• High levels of toxins, including heavy metals such as mercury, lead and arsenic, and organic toxins such as hexane, pentane and perchlorethylene. Toxins are pro-oxidants, and children with autism are poor detoxifiers. When the anti-oxidant defense is low, toxins build up. Higher levels of toxins worsen oxidative stress.
• Impaired energetics. The cell converts food from the diet into cellular energy in the mitochondria. If energy production in the mitochondria is sluggish, oxidative stress increases. The mitochondria are sensitive to damage by oxidants, including mercury. Once the mitochondria are damaged, they produce energy less efficiently, perhaps resulting in low tone and low arousal. Special brain scans and blood studies confirm problems with energy production in children with autism.
• High nitric oxide (NO) levels. Nitric oxide, the first free radical measured in children with autism, damages vitamin B12. Excess NO is associated with leaky gut, leakiness of the blood-brain barrier, and nerve cell death.
• Impaired nervous system function. Studies of brain tissue in those with autism and the presence of larger pupils suggest that one particular type of neurons, which are most susceptible to oxidative stress, are not functioning properly. Electrical recordings also point to oxidative injury to the retina, an anatomical extension of the brain.
• Actual tissue injury. Researchers report preliminary findings of increased lipofuscin in brain, oxidized fat in urine, and nitric oxide-altered protein in urine of autistic children, all direct signs of tissue injury from oxidative stress.

Can We Test for Oxidative Stress?

Blood, urine, stool and breath tests for oxidative stress are presently making their way from research to application. Measuring oxidative stress may help in understanding the causes of autism and in determining optimal doses and combinations of treatments.

What Treatments May Benefit Oxidative Stress?

Health care providers report promising new therapies which may benefit oxidative stress. Intravenous glutathione (GSH), n-acetyl cysteine (NAC), and vitamin C are all powerful anti-oxidants. Vitamin B12 injections could benefit by scavenging nitric oxide and by helping the body detoxify. Thiamine tetrahydrofurfuryl disulfide (TTFD) delivers high levels of the vitamin thiamine, which can lessen oxidative stress by boosting energy-producing enzymes blocked by NO and other oxidants. (For more on these treatments, see New Developments 8:3) Increasing metallothionein with dietary supplements is also very important since metallothionein is strongly anti-oxidant. (See New Developments 7:1). Finally, gluten- and casein-free diets are beneficial, by apparently reducing opioid levels. Under conditions of high levels of oxidative stress, opioids from casein and gluten may bind too tightly to receptors in the brain.

Viewing autism spectrum disorders in the context of oxidative stress creates some exciting new research and clinical possibilities.

Dr. McGinnis coordinates the Oxidative Stress in Autism Study; Principal Investigator: William Walsh. NIH author: Robert Salomon. Collaboraters: Bruce Ames, Allen Lewis, George Perry, Domenico Pratico, Aristo Vojdani. Sponsors: Alexander and Bo MacInnis.

[Initially published in New Developments: Volume 9, Number 2 - Winter, 2003-2004]