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

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 beta subunits in modulating these effects. To study the role of beta subunits of the Na+ channel we used a mouse line genetically lacking either the beta(1) or beta(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 mu M eslicarbazepine. We examined I-Nap in acutely isolated CA1 neurons and repetitive firing in hippocampal slices of mice lacking beta 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 beta(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 beta(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. (C) 2013 Elsevier B.V. All rights reserved.