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.