The effects of eslicarbazepine on persistent Na⁺ current and the role of the Na⁺ channel β subunits.

Summary Eslicarbazepine is the major active metabolite of eslicarbazepine acetate, a once-daily antiepileptic drug approved in Europe as adjunctive therapy for refractory partial-onset seizures in adults. This study was aimed to determine the effects of eslicarbazepine on persistent Na + currents ( I NaP ) and the role of β subunits in modulating these effects. To study the role of β subunits of the Na + channel we used a mouse line genetically lacking either the β 1 or β 2 subunit, encoded by the SCN1B or SCN2B gene, respectively. Whole cell patch-clamp recordings were performed on CA1 neurons in hippocampal slices under control conditions and application of 300 μM eslicarbazepine. We examined I NaP in acutely isolated CA1 neurons and repetitive firing in hippocampal slices of mice lacking β subunits and corresponding wild-type littermates. We found that eslicarbazepine caused a significant reduction of maximal I NaP conductance and an efficient reduction of the firing rate in wild-type mice. We have shown previously a paradoxical increase of conductance of I NaP caused by carbamazepine in mice lacking β 1 subunits in the subthreshold range, leading to a failure in affecting neuronal firing ( Uebachs et al., 2010 ). In contrast, eslicarbazepine did not cause this paradoxical effect on I NaP in SCN1B null mice. Consequently, the effects of eslicarbazepine on repetitive firing were maintained in these animals. These results indicate that eslicarbazepine exerts effects on I NaP similar to those known for carbamazepine. However, in animals lacking the β 1 Na + channel subunit these effects are maintained. Therefore, eslicarbazepine potentially overcomes a previously described putative mechanism of resistance to established Na + channel acting antiepileptic drugs.