Song J H, Narahashi T
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois, USA.
J Pharmacol Exp Ther. 1995 Dec;275(3):1402-11.
Pyrethroids exert their hyperexcitatory effects by prolonging the open time of individual neuronal sodium channels. Occupational exposure to pyrethroids frequently leads to abnormal skin sensation or paresthesia. Vitamin E is known to reduce the cutaneous paresthesia. However, the mechanism of action has been totally unclear. Because the sodium channel is the major target site of pyrethroids, it is possible that vitamin E interferes with pyrethroid modification of the sodium channel. Patch clamp experiments were performed using rat dorsal root ganglion neurons and cerebellar Purkinje cells. (+/-)-alpha-Tocopherol (vitamin E) selectively blocked the tetramethrin(type I pyrethroid)-modified sodium channels in a dose-dependent, but voltage-independent manner without affecting normal sodium channels. The concentration-response curves for tetramethrin modification of the sodium channels were shifted in the direction of higher concentrations by (+/-)-alpha-tocopherol in a competitive manner. Elevated depolarizing after-potential or repetitive after-discharges caused by tetramethrin were effectively blocked by (+/-)-alpha-tocopherol. (+/-)-alpha-Tocopherol did not reverse the tetramethrin-induced shift in the current-voltage curve for peak sodium current, but partially reversed the shift in the steady-state sodium channel inactivation curve. Vitamin A and its metabolic derivative, retinoic acid, slightly reduced both normal and tetramethrin-modified sodium currents. The selective block of tetramethrin-modified sodium channels by (+/-)-alpha-tocopherol is one of the important mechanisms underlying (+/-)-alpha-tocopherol alleviation of paresthesia.
拟除虫菊酯通过延长单个神经元钠通道的开放时间发挥其过度兴奋作用。职业性接触拟除虫菊酯常导致皮肤感觉异常或感觉异常。已知维生素E可减轻皮肤感觉异常。然而，其作用机制完全不清楚。由于钠通道是拟除虫菊酯的主要靶位点，维生素E有可能干扰拟除虫菊酯对钠通道的修饰。使用大鼠背根神经节神经元和小脑浦肯野细胞进行了膜片钳实验。（±）-α-生育酚（维生素E）以剂量依赖性但电压非依赖性方式选择性阻断胺菊酯（I型拟除虫菊酯）修饰的钠通道，而不影响正常钠通道。（±）-α-生育酚以竞争性方式使胺菊酯修饰钠通道的浓度-反应曲线向更高浓度方向移动。由胺菊酯引起 的去极化后电位升高或重复后放电被（±）-α-生育酚有效阻断。（±）-α-生育酚没有逆转胺菊酯诱导的峰值钠电流电流-电压曲线的偏移，但部分逆转了稳态钠通道失活曲线的偏移。维生素A及其代谢衍生物视黄酸略微降低正常和胺菊酯修饰的钠电流。（±）-α-生育酚对胺菊酯修饰钠通道的选择性阻断是（±）-α-生育酚减轻感觉异常的重要机制之一。
