Potential Block for Epilepsy: Researchers find new drug target

Most epilepsy treatments start after the disease has taken hold. A person might take anticonvulsant drugs to stop seizures or have surgery to remove a damaged portion of the brain. Now, using genetically engineered mice, scientists have identified a new target in the brain for potential drugs that could prevent epilepsy in the first place.

Epilepsy disturbs the signals that flow between nerve cells. During a seizure, intense, abnormally synchronized electrical impulses disrupt normal brain function. The condition can stem from a birth defect, stroke, or a head injury, but scientists don’t know its underlying mechanism.

“My guess is that despite the diversity of causes, there is a common thread,” says neurobiologist James O. McNamara of Duke University in Durham, N.C. He and other scientists suspect that a usually benign brain protein and its molecular docking site, or receptor, on nerve cells sometimes transform a normal brain into an epileptic one.

To explore that idea, McNamara and his team created one set of mice missing the suspect protein, called brain-derived neurotrophic factor, or BDNF, in the relevant portions of their brains. The group created another set of mice missing BDNF’s receptor. The scientists hypothesized that these two types of so-called knockout mice would develop epilepsy more slowly than normal mice do.

The researchers used a common laboratory method—bursts of short electrical shocks—to induce epilepsy in both groups of knockout mice and in some normal mice. Repeated shocks typically produce longer and longer brain disruptions. Eventually, the animals stop walking, begin nodding their heads and drooling, and ultimately have full-blown seizures.

The normal mice followed this trajectory, as expected, the team reports in the July 8 Neuron. The mice without BDNF, which researchers have presumed is important to epilepsy progression, also developed the disease.

“That was one of the surprises here,” says McNamara. “It blew us away.”

However, the receptor-knockout mice experienced small electrical disturbances in their brains but never progressed to seizures, no matter how many shocks the researchers applied.

“The complete lack of progression [to epilepsy] is surprising,” says Thomas P. Sutula, a neurologist at the University of Wisconsin–Madison. “It’s a pretty clear and convincing result. You don’t see that very often in a complex-systems disorder like epilepsy.”

BDNF’s receptor, also called TrkB, is a tantalizing target for new pharmaceuticals. If the receptor must be in operation for seizures to occur, a drug that disables it might prevent epilepsy in people vulnerable to the disease. McNamara is already trying to identify small molecules to block BDNF or other brain chemicals from docking to and activating the receptor.

Developing such a molecule isn’t conceptually difficult, says neurologist Philip A. Schwartzkroin of the University of California, Davis. “We do that all the time in pharmacology,” he notes.

The receptor’s role needs to be tested in other animal models of epilepsy before scientists can determine its importance, Schwartzkroin says.