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CNS receptor could be key to preventing epilepsy

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Inhibiting TrkB prevents the brain from becoming epileptic.--Courtesy of Gumei Liu and James McNamara

Researchers at Duke Medicine have found a way to prevent epilepsy in mice that have already experienced a long period of seizures--a feat that could help scientists develop new drugs to treat the serious neurological disorder.

Their findings, published online in the journal Neuron on June 20, identified a receptor in the nervous system--TrkB--that may play a central role in transforming the brain from normal to epileptic.

"With respect to common disorders of the neurological system, there is no effective preventive measure for any of them," said study author Dr. James McNamara, professor of neurobiology at Duke Medicine, in an interview with FierceBiotechResearch.

The only drugs available for epileptic patients are designed to reduce the symptoms of the disease and typically target ion channels, a different kind of target than TrkB. That's because scientists haven't been able to pinpoint a molecular target to develop preventive drugs.

Characterized by recurring seizures, McNamara calls epilepsy a "serious public health problem." The most common form of epilepsy, temporal lobe epilepsy--when seizures occur in the region of the brain where memories are stored and language, emotions and senses are processed--can be devastating, as the disease impairs awareness and can cause behavioral problems. Even taking current drugs, some patients with temporal lobe epilepsy still experience seizures. 

Research has shown that people with severe temporal lobe epilepsy have an initial episode of prolonged seizures, usually in childhood, followed by a period of recovery without seizures before developing recurring temporal lobe seizures.

In previous studies, scientists found that inducing prolonged seizures in healthy animals can cause them to become epileptic, leading McNamara and his colleagues to believe that this episode of prolonged seizures is connected to the development of the disease in humans. Using this premise, as well as previous research that marked the TrkB receptor as a potential player in epilepsy, McNamara and his team compared normal mice to genetically altered ones, in which a drug, 1NMPP1, inhibited the TrkB pathway in their brains. When the researchers induced prolonged seizures, both groups of mice developed epilepsy. When mice were given 1NMPP1 for two weeks after the period of seizures, the drug prevented epilepsy in the genetically altered mice but not in the normal ones.

"This study demonstrates that one can intervene during this episode of prolonged seizures and prevent animals from becoming epileptic," McNamara said.

The findings are significant for a few reasons. First, it means scientists now have a target for drug discovery. Second, it means that if the drug works similarly in humans, any unwanted effects of the drug would be limited over time. That would be a benefit to patients, who wouldn't have to take antiseizure drugs throughout the course of their lives.

McNamara told FierceBiotechResearch that the next step is to continue testing the drug in animals to determine precisely when the TrkB inhibitor must be administered to prevent epilepsy and whether the therapy needs to be continued for two weeks or if that period could be reduced to a shorter window of time.

- here's the study abstract
- read the press release

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