Possible repositioning of an antipsychotic drug for the treatment of epilepsy

Epilepsy is one of the most common and disabling brain disorders, affecting about 1 percent of the population of all ages, often with concomitant psychiatric and neurocognitive problems. Although several classes of anticonvulsant drugs (ASMs) are available, seizures are drug-resistant, i.e., not adequately controlled, in 30% of patients. Therefore, the identification of new mechanisms of action for ASMs represents a crucial need. Among these, the activation of voltage-dependent Kv7 potassium channels expressed in neurons and involved in genetically-determined forms of neonatal-onset childhood epilepsies is of particular interest; unfortunately, the only drug so far approved for the treatment of adult epilepsy that acted by this mechanism of action (called retigabine) has recently been withdrawn from the market due to toxicities unrelated to the mechanism of action.

Through a multidisciplinary approach that combined high-throughput drug screening techniques, electrophysiological methods, molecular modeling and animal model studies, the research team coordinated by Professor Maurizio Taglialatela together with Professors Francesco Miceli and Vincenzo Barrese, researcher Natascia Guida postdoc Lidia Carotenuto and doctoral student Giusy Carleo of the Pharmacology Section of the Department of Neuroscience, Reproductive and Odontostomatological Sciences at the Federico II University, identified (among more than 8,000 biologically active molecules) a molecule called JNJ-37822681 (JNJ), originally developed as an antipsychotic, as a potent activator of Kv7 channels. JNJ, by activating Kv7 channels, reduces the electrical activity of neurons differentiated from human cells obtained from control subjects and from patients with mutations in Kv7 channels. The work also showed that JNJ exerts anticonvulsant activity in two animal models of seizures widely used for screening ASMs.

In conclusion, these data suggest that JNJ, a molecule already shown to be safe in humans, represents a promising drug for the treatment of epilepsy, with particular reference to the 30 percent of epilepsy patients who have psychiatric or genetically based comorbidities.

The results of that study were recently published in the prestigious British Journal of Pharmacology.

The study, which was also funded by the MNESYS Neuroscience and Neuropharmacology Extended Partnership Project, of which the Federico II University is coordinating Spoke 3, involved the collaboration of researchers from the Universities of Salerno, "Magna Graecia" of Catanzaro, Antwerp (Belgium) and the Fraunhofer Institute (Germany).

The fast-dissociating _D2 antagonist antipsychotic JNJ-37822681 is a neuronal Kv7 channel opener: Potential repurposing for epilepsy treatment