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 IC₅₀ values of 78 and 34 μM found in GH₃ 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.