Comparative study of lacosamide and classical sodium channel blocking antiepileptic drugs on sodium channel slow inactivation

Many antiepileptic drugs (AEDs) exert their therapeutic activity by modifying the inactivation properties of voltage-gated sodium (Nav) channels. Lacosamide is unique among AEDs in that it selectively enhances the slow inactivation component. Although numerous studies have investigated the effects of AEDs on Nav channel inactivation, a direct comparison of results cannot be made because of varying experimental conditions. In this study, the effects of different AEDs on Nav channel steady-state slow inactivation were investigated under identical experimental conditions using whole-cell patch-clamp in N1E-115 mouse neuroblastoma cells. All drugs were tested at 100 mu M, and results were compared with those from time-matched control groups. Lacosamide significantly shifted the voltage dependence of Nav current (INa) slow inactivation toward more hyperpolarized potentials (by -33 +/- 7 mV), whereas the maximal fraction of slow inactivated channels and the curve slope did not differ significantly. Neither SPM 6953 (lacosamide inactive enantiomer), nor carbamazepine, nor zonisamide affected the voltage dependence of INa slow inactivation, the maximal fraction of slow inactivated channels, or the curve slope. Phenytoin significantly increased the maximal fraction of slow inactivated channels (by 28% +/- 9%) in a voltage-independent manner but did not affect the curve slope. Lamotrigine slightly increased the fraction of inactivated currents (by 15% +/- 4%) and widened the range of the slow inactivation voltage dependence. Lamotrigine and rufinamide induced weak, but significant, shifts of INa slow inactivation toward more depolarized potentials. The effects of lacosamide on Nav channel slow inactivation corroborate previous observations that lacosamide has a unique mode of action among AEDs that act on Nav channels. (c) 2012 Wiley Periodicals, Inc.