Drug Prevents Abnormalities That Lead To Seizures, Mouse Study Shows

Now scientists at Washington University School of Medicine in St. Louis have taken the first step toward developing another option. They've used a drug to prevent the brain abnormalities that lead to seizures in mice with an inherited form of epilepsy.

Working in a mouse model of tuberous sclerosis, an inherited human condition that causes seizures, researchers showed that regular doses of the drug rapamycin prevented the mice from seizing. The treatment also blocked the development of structural abnormalities in the brain and extended lifespan.

"One percent of the general population has epilepsy, and one-third of those patients don't respond well to current treatments," says senior author Michael Wong, M.D., Ph.D., assistant professor of neurobiology and anatomy, of neurology and of pediatrics. "We need to look for new treatments that do more than just alleviate the symptoms. We have to find ways to prevent the underlying brain abnormalitites that lead to seizures, and this is a first step in that direction."

Epilepsy can be induced by dozens of different causes including various forms of brain injury, genetic mutations and exposure to environmental insults.

Tuberous sclerosis (TS) is one of the most common genetic causes of epilepsy. Epidemiologists estimate that it occurs in one birth in every 6,000. In addition to seizures, the condition may cause tumors in the brain and other organs, autism, learning disabilities, skin abnormalities and lung and kidney disease.

Scientists have linked TS to mutations in one of two genes, TSC1 or TSC2. To better understand and seek new treatments for tumors caused by TS, Wong's colleague and co-author David Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology and co-director of the neuro-oncology program at the Siteman Cancer Center, created a mouse model of TS.

Research by other scientists showed that the genes mutated in TS overactivate mTOR (mammalian target of rapamycin), a protein that regulates several aspects of cell growth and proliferation. Those results led to clinical trials currently underway to see if rapamycin, an FDA-approved drug that has been in use for more than a decade, can block tumor growth by decreasing activation of the mTOR pathway.

"We reasoned that mTOR might also be abnormally regulating genes that produce neurotransmitter receptors, ion channels, and other proteins involved in brain cell communication, and that this might contribute to the seizures we see in TS patients," Wong says. "If that's the case, rapamycin should decrease the chance of seizures by decreasing mTOR activation."

The mouse line developed by Gutmann's lab normally starts having seizures at 1 to 2 months of age. When Ling-Hui Zeng, M.D., Ph.D., a postdoctoral fellow in Wong's lab, gave a group of the mice regular doses of rapamycin starting at 2 weeks of age, they were seizure-free. A closer look at the structure of brain cells in the treated mice revealed that the drug had prevented the development of structural and molecular abnormalities in brain cells known as astrocytes.

Normally the mice die at 3-4 months of age, but with regular rapamycin doses they were still alive at 6 months. At that point, Wong's laboratory took them off the rapamycin, and the mice started seizing for the first time.

In separate experiments, scientists found that giving rapamycin to mice later in their development could still partially reverse brain abnormalities and decrease seizures.

"These results support the initiation of clinical trials to test this drug's ability to alleviate seizures from tuberous sclerosis in human patients," says Wong.

Wong's follow-up plans focus on further studies of mTOR's links to seizures in TS. Because of mTOR's wide-ranging effects on a variety of proteins and pathways, Wong wants to identify new drug targets that are more directly responsible for triggering seizures in TS patients.

Journal reference: Zeng L-H, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Annals of Neurology, advance online edition, April 3, 2008.

Funding from the National Institutes of Health and the Tuberous Sclerosis Alliance supported this research.