Electrophysiological Effects of Eslicarbazepine on Selected Nav1.6 Variants Associated with Developmental and Epileptic Encephalopathies
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Major problems with the current anti-epileptic drugs (AED) are resistance, inability to modify the course of the disease and side effects profiles, which rises the need for improved AEDs for all age group of patients. Eslicarbazepine acetate is a sodium channel blocker AED and is superior to some other well-known AEDs in terms of selectivity, safety, efficacy and effects on sodium channels. In our study, to assess eslicarbazepine (S-Lic) effects, we chose wild-type Nav1.6 channels along with three SCN8A gene variants known to be causing developmental and epileptic encephalopathies (DEE), (M1760I, G1475R, and A1622D). Electrophysiological analyses were performed by using two heterologous expression systems (neuroblastoma cell line (ND7/23) for voltage-clamp recordings, and primary neuronal cultures for current-clamp recordings). 300 μM of S-Lic reduced maximal firing rates in neurons having wild-type NaV1.6 channels. S-Lic enhanced slow inactivation kinetics in all DEE variants tested, but also displayed variant-specific effects by modifying biophysical properties of tested variant channels. S-Lic treatment increased the kinetics of fast inactivation and reduced the persistent current in A1622D variant. Additionally, S-Lic decreased neuronal firing rate to that of wild-type in M1760I variant. Those findings emphasize the significance of individualized therapy, and prompt the potential use of Eslicarbazepine acetate, -taking into account its unique effects on epileptogenesis and slow inactivation, and its better safety and therapeutic index – as an alternative option against some SCN8A (NaV1.6) variants causing DEE.