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 (R)), an anti-convulsant and analgesic, on voltagegated 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 mu M found in GH(3) cells and of 112 and 26 mu M 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 (tau) 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 tau'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 tau 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.