New Drug Target Reduces Seizures in Mice

by Kayt Sukel

August 12, 2009

Despite a variety of available drug treatments, many people who have epilepsy still are unable to control their seizures with medication. New research suggests a molecular mechanism that seems to “reset” neurons may and offer another avenue for treatment.

More than 3 million people in the United States have epilepsy, according to the Epilepsy Foundation. The condition is characterized by abnormal electrical activity in the brain that leads to progressive—and sometimes very strong—seizures.

Even with the development of many new epilepsy drugs in the past few decades, both patients and clinicians often are frustrated when trying to find the right medication, says Gregory Bergey, a clinical neurologist and director of the Johns Hopkins Epilepsy Center.

“The fact is, since 1993 and the development of about a dozen new drugs, we just haven’t made that many more people seizure-free,” Bergey says. “We can say that new medications are better tolerated and have fewer side effects. But what we can’t say is why it is so difficult to get such a large proportion of people with the disease seizure-free. Are we missing some important mechanism in how epilepsy develops that could be addressed?”

One such potential mechanism involves the BK channel, an ion channel that conducts potassium across cell membranes and plays some part in neuronal action potentials, the electrochemical responses that help carry signals across the synapse.

“BK channels help to repolarize action potentials in neurons,” says Robert Brenner, a physiologist at the University of Texas Health Science Center at San Antonio. “In neurons that fire frequently, BK channels may ‘reset’ the neuron to be able to quickly fire again.”

Alison Barth, a neuroscientist at Carnegie Mellon University, and her colleagues found that abnormal BK channel activity is linked to epileptogenesis, the development of epilepsy. People who have a rare genetic variant that results in changes to BK channel function are likely to suffer from seizures. Barth’s laboratory also found that seizures themselves can change the way BK channels operate.

“If abnormal activity is linked to epileptogenesis, then we thought that maybe reducing that abnormal activity by way of blocking the BK channel could halt the process of epileptogenesis and, of course, reduce the emergence of epilepsy,” she says. “And that’s just what happened.” Their work is published in the April issue of Epilepsia.

Using mice bred to show signs of epilepsy, Barth and her colleagues treated the animals with paxilline, an experimental drug that blocks the action at the BK channel. They found that the drug could reduce or prevent induced seizures. Even more notable: after giving the drug to normal animals, the researchers observed no noticeable effects.

“In an animal that had normal brain activity, there was no effect of the paxilline. And that was really exciting,” Barth says. “It suggests that these drugs only have an effect if the brain was already somehow compromised and on its way to develop the abnormal circuitry that might predispose it to epilepsy.”

Barth cautions that the results are preliminary, and researchers still have a lot to learn before paxilline might be used to treat people.

“Our next steps are to better understand the molecular basis for this effect,” she says. “I think there are specific changes in the expression of BK channels that lead to seizures. And if we understand that better, we can design the right kind of drugs to target those abnormal BK channels, leaving the other ones present throughout the body alone.”

Bergey says such research is needed to develop future drugs to treat epilepsy.

“The BK channel antagonist is, conceptually, very exciting,” he says. “I can’t tell you if it will be a magic bullet—there’s a lot that happens between the bench and the bedside—but it’s definitely a novel mechanism that’s worth a closer look.”