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May 2011

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Exercise may protect the brain from chemical-induced injury

By Robin Arnette
May 2011

Jean Harry, Ph.D.

Harry said that in terms of inflammation, her studies show that the brain and the rest of the body are not separated, but seem to work together. (Photo courtesy of Steve McCaw)

Scientists have known for years that exercise has positive effects on human health, such as the prevention of heart disease, diabetes, and obesity, as well as promoting recovery following a brain injury as in stroke. But, recent research using mice suggests that exercise may also offer some protection against environmental toxicants and neurodegenerative diseases by reducing inflammation in the brain.

Researchers at NIEHS and the University of Alabama at Birmingham assigned adult male mice to two groups. The experimental mice had access to a running wheel, while the sedentary control mice did not. After two weeks, mice from both groups were injected with either saline or trimethyltin (TMT), an organic tin compound used to experimentally examine chemical damage to the brain.

"Even a small amount of TMT will destroy the hippocampus in the brain of a young animal, compromising its learning and memory capability," said Jean Harry, Ph.D., principal investigator in the NIEHS Laboratory of Toxicology and Pharmacology and corresponding author on the paper.

Since TMT causes similar damage in humans and mice, Harry and her research team used TMT as a model system for studying brain injury involving neuroinflammation. According to Harry, TMT is commercially used as a plastic stabilizer, but recently, many American manufacturers have replaced TMT with other compounds, such as dimethyltin (DMT), in the production of polyvinyl chloride (PVC) tubing.

"Outside of the U.S., TMT continues to cause accidental poisoning in humans," Harry said. "Additionally, Koichi Furuhashi, Ph.D., and his colleagues at Nagoya University Graduate School of Medicine in Japan, have shown that metabolic processes can add a methyl group to DMT to form TMT within the body, which may now raise concern about DMT exposure."

The role of inflammation

Twenty-four hours after the TMT injection, the control mice exhibited an increase in both anti-inflammatory and pro-inflammatory factors. They also suffered a loss of hippocampal cells known as dentate granule neurons. According to Harry, these cells are important because they serve as a gateway for a person's experiences and short-term memory, and they are one of the few cell types that the brain continuously makes throughout a person's life.

In contrast, the mice that used the running wheel for two weeks prior to the injection experienced significantly less brain damage, but more importantly, the levels of anti-inflammatory factors, such as interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA) increased in the hippocampus of these animals. As a result, the amount of pro-inflammatory molecules in their brains dropped dramatically. Harry said her findings support previous work from other labs that showed exercise prompts muscle and brain tissue to produce IL-6, which turns off tumor necrosis factor-alpha (TNF-alpha), a major pro-inflammatory signal. Her research is the first demonstration that IL-6 production serves to prevent neuronal damage with exercise.

She explained the outcome this way: "If cell death occurs in the brain as a result of chemical exposure, neuroinflammation is a likely result. But, exercise can diminish this effect by producing molecules that repress this signal and possibly prevent neuronal death or promote repair."

Workouts may alleviate neural disorders

Harry added that TNF-alpha levels rise with any inflammatory event in the body, for example, in the case of rheumatoid arthritis. In the brain, however, this process is highly regulated. Since neuroinflammation is a component of many neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and autism, she believes the combination of exercise physiology and neuroscience research may allow investigators to identify new pathways and treatments that regulate the good and bad aspects of neuroinflammation.

Harry mentioned another exciting finding from her studies - the relatively brief span it took to see results from the exercise. "These are normal young adult animals, and two weeks of exercise on a running wheel is a short time for an exercise model. Most of them require four to five weeks, so we're showing a significant physiological change in an abbreviated period of time."

Citation: Funk JA, Gohlke J, Kraft AD, McPherson CA, Collins JB, Harry GJ.( Exit NIEHS 2011. Voluntary exercise protects hippocampal neurons from trimethyltin injury: Possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity. Brain Behav Immun; doi:10.1016/j.bbi.2011.03.012 [Online 22 March 2011].

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