Abstracts

Rationale: The efficacy of adjunctive eslicarbazepine acetate (ESL) in reducing the frequency of partial-onset seizures and tolerability in adults receiving carbamazepine (CBZ) or another antiepileptic drug (AED) was similar (Epilepsia, 50, 454-463, 2009; Epilepsy Res., 89, 278-285, 2010). On the other hand, a large number of subjects experienced neurotoxicity when lacosamide (LCM) was added to another voltage-gated sodium channel (VGSC) blocking AED (Epilepsy Behav, 16, 423-425, 2009; Epilepsy Behav, 20, 20-23, 2011). Advice was given to reduce concomitantly the conventional VGSC-blocking AEDs during LCS uptitration in cases of neurotoxicity (Epilepsy Behav, 20, 20-23, 2011). This study was aimed to determine the effects of eslicarbazepine, the major active metabolite of ESL, CBZ, oxcarbazepine (OXC) and LCM on the fast and slow inactivated sates of VGSC. Methods: The whole-cell patch-clamp technique was used to investigate the effects of eslicarbazepine CBZ, OXC and LCM (at 250 μM) on sodium channels endogenously expressed in N1E-115 cells, in conditions of fast and slow inactivation of sodium currents. Results: At a concentration of 250 µM, the voltage dependence of the fast inactivation was not influenced by eslicarbazepine, whereas LCM, CBZ and OXC shifted the V0.5 value by -4.8 mV, -12.0 mV and -16.6 mV, respectively. Eslicarbazepine- and LCM-treated fast-inactivated channels recovered similarly to control conditions (Δt = 11 ms), whereas CBZ- and OXC-treated channels required longer pulses to recover (Δt = 391 ms). CBZ and OXC shifted by -4.6 mV and -28.1 mV the voltage dependence of the slow inactivation, whereas for eslicarbazepine and LCM the shift of the voltage dependence of the slow inactivation (V0.5) was -31.2 mV and -53.3 mV, respectively. For eslicarbazepine, LCM, CBZ and OXC, the affinity to the slow inactivated state was 5.9, 10.4, 1.7 and 1.8 times higher than to the channels in the resting state, respectively. For eslicarbazepine, LCM, CBZ and OXC, the time constants for entering the slow inactivated state were 7.00, 4.54, 14.49 and 12.36 s, respectively. Conclusions: Eslicarbazepine does not share with CBZ and OXC the ability to alter fast inactivation of VGSC, but rather appears to modify the kinetics and voltage-dependence of slow inactivation states. Both eslicarbazepine and LCM reduce VGSC availability through enhancement of slow inactivation, but LCM demonstrated higher interaction with VGSC in the resting state, with fast inactivation gating and shorter time to enter in the slow inactivated state.