Abstracts

Rationale: Pharmacoresistance to antiepileptic drugs (AEDs) is a problem affecting up to 30% of chronic epilepsy patients. For classical AEDs, a loss of use-dependent blocking of voltage-gated sodium channels in experimental as well as human epilepsy has been demonstrated as a potential mechanism of pharmacoresistance. For this reason, there is an ongoing interest for development of new AEDs overcoming pharmacoresistance. One candidate drug to reach this goal is eslicarbazepine acetate (ESL), a third-generation member of the dibenzazepine family of AEDs. After oral administration, ESL is hydrolyzed to its major active metabolite eslicarbazepine (also (S)-licarbazepine; S-Lic). It has previously been demonstrated that S-Lic has maintained use-dependent blocking effects both in human and experimental epilepsy. Furthermore antiepileptogenic activity has been reported. Previously the efficacy of S-Lic in chronic epileptic tissue has been examined for repetitive action potential firing as well as fast sodium channel inactivation kinetics in dentate gyrus granule cells (DGCs). Methods: We have investigated effects of S-Lic on slow inactivation processes of sodium currents in DGCs. We have used voltage-clamp recordings in isolated dentate granule cells of control vs. chronically epileptic rats (pilocarpine model of epilepsy) as well isolated DGCs from temporal lobe epilepsy patients obtained from specimens resected during epilepsy surgery.  Results: We examined the effects of 100 and 300 µM S-Lic on entry of sodium channels into slow inactivation. S-Lic increased the fraction of channels entering slow inactivation, with the biggest effects being observed for 10 s depolarizing prepulses. There were no significant differences between sham-control and epileptic rat groups and TLE patients. S-Lic did not alter the time course of recovery from slow inactivation. We further tested the voltage-dependence of slow inactivation using 10 second depolarizing prepulses to various voltages. Concentrations of 100 and 300 µM S-Lic caused pronounced shifts in the voltage-dependence of slow inactivation. The magnitude of this effect was not different between the experimental groups.  Conclusions: From these data we conclude that S-Lic exerts potent effects on the voltage-dependence of slow inactivation, in addition to the previously described effects on fast inactivation. Additionally, we show that these effects on slow inactivation are maintained, both in chronic epilepsy models and in neurons from human epileptic tissue.  Funding: This study was funded by Bial - Portela & Cª, SA.