Effective Modulation by Lacosamide on Cumulative Inhibition of I(Na) during High-Frequency Stimulation and Recovery of I(Na) Block during Conditioning Pulse Train

The effects of lacosamide (LCS, Vimpat(®)), an anti-convulsant and analgesic, on voltage-gated Na(+) current (I(Na)) were investigated. LCS suppressed both the peak (transient, I(Na(T))) and sustained (late, I(Na(L))) components of I(Na) with the IC(50) values of 78 and 34 μM found in GH(3) cells and of 112 and 26 μM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent I(Na) (I(Na(P))) during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of I(Na(T)) or I(Na(L)) during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the I(Na) block elicited by the preceding conditioning train can be fitted by two exponential processes, while the single exponential increase in current recovery without a conditioning train was adequately fitted. The fast and slow τ’s of recovery from the I(Na) block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window I(Na) (I(Na(W))) during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of I(Na) activated by pulse train stimulation, and veratridine reversed its decrease in the decaying τ value in current inactivation. The docking results predicted the capability of LCS binding to some amino-acid residues in sodium channels owing to the occurrence of hydrophobic contact. Overall, our findings unveiled that LCS can interact with the sodium channels to alter the magnitude, gating, voltage-dependent hysteresis behavior, and use dependence of I(Na) in excitable cells.