Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Int J Mol Sci. 2022 Oct 8;23(19):11966. doi: 10.3390/ijms231911966.
The effects of lacosamide (LCS, Vimpat), an anti-convulsant and analgesic, on voltage-gated Na current () were investigated. LCS suppressed both the peak (transient, ) and sustained (late, ) components of with the IC values of 78 and 34 μM found in GH cells and of 112 and 26 μM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent () during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of or during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the 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 block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window () during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of 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 in excitable cells.
拉考沙胺（LCS，Vimpat）是一种抗惊厥和镇痛药物，研究其对电压门控钠电流（）的影响。LCS 抑制峰值（瞬态，）和持续（晚期，）组成的，其在 GH 细胞中的 IC 值分别为 78 和 34 μM，在 Neuro-2a 细胞中的 IC 值分别为 112 和 26 μM。在 GH3 细胞中，三角形斜坡脉冲期间持续（）的电压依赖性滞后现象明显减弱，LCS 进一步缩短了去极化脉冲串期间的或的衰减时间常数（τ）。由先前条件作用的训练诱发的阻断后的恢复时间过程可以拟合为两个指数过程，而没有条件作用的训练时电流恢复的单指数增加可以很好地拟合。在 LCS 存在的情况下，由相同条件作用方案引起的阻断后的快速和慢速τ的恢复。在 Neuro-2a 细胞中，LCS 降低了快速斜坡脉冲期间的瞬时窗口（）的强度。Tefluthrin 可以逆转这种减少。此外，LCS 加速了由脉冲串刺激激活的的失活时间过程，并且 veratridine 逆转了其电流失活中衰减 τ 值的降低。对接结果预测了 LCS 由于发生疏水性接触而与钠通道中的一些氨基酸残基结合的能力。总的来说，我们的研究结果表明，LCS 可以与钠通道相互作用，改变可兴奋细胞中电流的幅度、门控、电压依赖性滞后行为和使用依赖性。
