Rapamycin epilepsy-prevention effect may be widely applicable

Jun 1 2009

A drug with potential to prevent epilepsy caused by a genetic condition may also help prevent more common forms of epilepsy caused by brain injury, according to researchers at Washington University School of Medicine in St. Louis.

Scientists found that the FDA-approved drug rapamycin blocks brain changes believed to cause seizures in rats. In a paper last year, the same group showed that rapamycin prevents brain changes in mice triggered by one of the most common genetic causes of epilepsy, tuberous sclerosis (TS).

"We hope to shift the focus from stopping seizures to preventing the brain abnormalities that cause seizures in the first place, and our results in the animal models so far have been encouraging," says senior author Michael Wong, M.D., Ph.D.

The study was published in The Journal of Neuroscience on May 27.

One percent of the population has epilepsy, which can result from genetic mutations, brain injuries and environmental insults. According to Wong, one-third of that group does not respond well to current anti-seizure medications.

"Researchers have traditionally tested potential epilepsy drugs on animals that were already having seizures," Wong says. "We may be able to improve our success rate by stepping back a little and trying to find a treatment that can halt the disease process prior to the start of seizures."

In earlier studies of TS, Wong and others showed that proteins involved in TS overactivate mTOR (mammalian target of rapamycin), a powerful regulatory protein. Wong speculated that mTOR might influence proteins involved in communication between brain cells, which could explain why TS causes seizures.

To test the theory, he gave rapamycin to mice with a TS gene mutation. The drug binds to mTOR, reducing its ability to activate other genes and proteins. Mice that received the drug were seizure-free and lived longer.

For the new study, Ling-Hui Zeng, Ph.D., a postdoctoral fellow, studied an animal model of epilepsy created by giving rats a drug known as kainate. Exposure to the drug initially causes a prolonged seizure. A few days later, the rats begin having spontaneous seizures. Research has previously shown that kainate causes brain cell death and the creation of new brain cells, and that some surviving brain cells grow multiple new branches, a phenomenon called mossy fiber sprouting. Scientists have speculated that this new and erratic growth of nerve cell branches may help promote the continuous chaotic nerve cell firing that takes place during seizures.

Zeng began her studies by showing that kainate causes an increase in a marker for mTOR activity during the initial seizure; this increase returned as rats began to develop spontaneous seizures days later and suggested that rapamycin might help prevent brain changes that underlie seizures.

When Zeng gave the rats rapamycin prior to kainate, the rats still had the initial seizure, but brain cell death, new brain cells and mossy fiber sprouting all decreased, and the later spontaneous seizures were also significantly reduced. Rats that received rapamycin after the initial seizure caused by kainate still lost and gained brain cells, but they had less mossy fiber sprouting and experienced fewer subsequent seizures.

"The fact that rapamycin had beneficial effects even after the first seizure is particularly exciting, because it suggests that if similar phenomena occur in the human brain, treating patients with mTOR inhibitors after a brain injury might reduce the chances of developing epilepsy," says Wong. "This may be particularly important for the surge of veterans returning with traumatic brain injuries from Iraq and Afghanistan."

Rapamycin is currently being evaluated in clinical trials as a treatment for the brain tumors caused by TS. Wong believes the new paper will add impetus for trials to test rapamycin and other mTOR inhibitors as epilepsy prevention drugs.