Eslicarbazepine, a third-generation anti-seizure medication, inhibits INa but stimulates IK(M)

Abstract

Eslicarbazepine (ESL) is a new antiseizure medication used to treat focal epilepsy. It is not entirely clear how ESL affects the magnitude and gating kinetics of membrane ionic currents, although a few reports have demonstrated its ability to suppress voltage-gated Na⁺ currents (I_Na). With the aid of patch clamp technology, docking prediction, and simulation modeling, this study was conducted to investigate the potential modifications through which ESL may induce on ionic currents, including I_Na, M-type K⁺ current (I_K(M)), and erg-mediated K⁺ current (I_K(erg)), in hippocampal neurons. ESL distinctly inhibited transient I_Na (I_Na(T)) and late I_Na (I_Na(L)), demonstrating greater potency against I_Na(L). ESL shifted the steady-state inactivation curve of I_Na(T) leftward without altering its steepness or activation curve. Additionally, ESL attenuated the tefluthrin-induced enhancement of voltage-dependent hysteresis (Hys_(V)) of persistent I_Na (I_Na(P)).

ESL increased I_K(M) in a concentration-dependent manner, shifting its steady-state activation curve toward more depolarized potentials and enhancing Hys(V) strength. It also increased the activity and mean open time of I_K(M) without affecting single-channel conductance. Minimal changes were observed in the magnitude of I_K(erg). Predicted docking analysis revealed that ESL binds to the hNa_V1.7 channel via hydrogen bonds and hydrophobic contacts. Simulation modeling using hippocampal CA1 pyramidal neurons demonstrated that ESL's inhibition of I_Na and stimulation of I_K(M), along with changes in their Hys(V), modulate neuronal action potential firing. Overall, these findings highlight ESL's dual effects on I_Na and I_K(M), revealing mechanisms that likely contribute to its efficacy in treatment of epilepsy.