Inhibitory effect of eslicarbazepine acetate and S-licarbazepine on Nav1.5 channels

Eslicarbazepine acetate (ESL) is a dibenzazepine anticonvulsant approved as adjunctive treatment for partial-onset epileptic seizures. Following first pass hydrolysis of ESL, S-licarbazepine (S-Lic) represents around 95 % of circulating active metabolites. S-Lic is the main enantiomer responsible for anticonvulsant activity and this is proposed to be through the blockade of voltage-gated Na + channels (VGSCs). ESL and S-Lic both have a voltage-dependent inhibitory effect on the Na + current in N1E-115 neuroblastoma cells expressing neuronal VGSC subtypes including Na v 1.1, Na v 1.2, Na v 1.3, Na v 1.6 and Na v 1.7. ESL has not been associated with cardiotoxicity in healthy volunteers, although a prolongation of the electrocardiographic PR interval has been observed, suggesting that ESL may also inhibit cardiac Na v 1.5 isoform. However, this has not previously been studied. Here, we investigated the electrophysiological effects of ESL and S-Lic on Na v 1.5 using whole-cell patch clamp recording. We interrogated two model systems: (1) MDA-MB-231 metastatic breast carcinoma cells, which endogenously express the ‘neonatal’ Na v 1.5 splice variant, and (2) HEK-293 cells stably over-expressing the ‘adult’ Na v 1.5 splice variant. We show that both ESL and S-Lic inhibit transient and persistent Na + current, hyperpolarise the voltage-dependence of fast inactivation, and slow the recovery from channel inactivation. These findings highlight, for the first time, the potent inhibitory effects of ESL and S-Lic on the Na v 1.5 isoform, suggesting a possible explanation for the prolonged PR interval observed in patients on ESL treatment. Given that numerous cancer cells have also been shown to express Na v 1.5, and that VGSCs potentiate invasion and metastasis, this study also paves the way for future investigations into ESL and S-Lic as potential invasion inhibitors.