title: The effects of eslicarbazepine on persistent Na⁺ current and the role of the Na⁺ channel β subunits.
abstract: 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 (INaP) 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 β1 or β2 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 INaP 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 INaP conductance and an efficient reduction of the firing rate in wild-type mice. We have shown previously a paradoxical increase of conductance of INaP caused by carbamazepine in mice lacking β1 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 INaP 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 INaP similar to those known for carbamazepine. However, in animals lacking the β1 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.
authors.affiliation: University of Bonn, Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Doeser
authors.affiliation: BIAL - Portela & Ca. SA, S. Mamede do Coronado, Portugal; Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
authors.affiliation: University of Bonn, Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, Bonn, Germany. Electronic address: heinz.beck@ukb.uni-bonn.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Beck
authors.affiliation: University of Bonn, Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, Bonn, Germany; University of Bonn, Department of Neurology, Bonn, Germany.
authors.forename: Mischa
authors.initials: M
authors.lastname: Uebachs
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003984:Dibenzazepines / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit / Q000502:physiology*
chemical_list: D000927:Anticonvulsants; D003984:Dibenzazepines; C524974:Scn1b protein, mouse; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; C571001:eslicarbazepine
keywords: Carbamazepine; Epilepsy; Eslicarbazepine; I(NaP); Persistent sodium current; Sodium channel beta subunits