Wang Ze-Jun, Tabakoff Boris, Levinson Simon R, Heinbockel Thomas
Department of Anatomy, Howard University College of Medicine, Washington 20059, DC, USA.
Department of Pharmacology, University of Colorado Denver School of Medicine, Aurora 80045, CO, USA.
Acta Pharmacol Sin. 2015 Jul;36(7):791-9. doi: 10.1038/aps.2015.26. Epub 2015 Jun 8.
Methyl eugenol is a major active component extracted from the Chinese herb Asari Radix et Rhizoma, which has been used to treat toothache and other pain. Previous in vivo studies have shown that methyl eugenol has anesthetic and antinociceptive effects. The aim of this study was to determine the possible mechanism underlying its effect on nervous system disorders.
The direct interaction of methyl eugenol with Na(+) channels was explored and characterized using electrophysiological recordings from Nav1.7-transfected CHO cells.
In whole-cell patch clamp mode, methyl eugenol tonically inhibited peripheral nerve Nav1.7 currents in a concentration- and voltage-dependent manner, with an IC50 of 295 μmol/L at a -100 mV holding potential. Functionally, methyl eugenol preferentially bound to Nav1.7 channels in the inactivated and/or open state, with weaker binding to channels in the resting state. Thus, in the presence of methyl eugenol, Nav1.7 channels exhibited reduced availability for activation in a steady-state inactivation protocol, strong use-dependent inhibition, enhanced binding kinetics, and slow recovery from inactivation compared to untreated channels. An estimation of the affinity of methyl eugenol for the resting and inactivated states of the channel also demonstrated that methyl eugenol preferentially binds to inactivated channels, with a 6.4 times greater affinity compared to channels in the resting state. The failure of inactivated channels to completely recover to control levels at higher concentrations of methyl eugenol implies that the drug may drive more drug-bound, fast-inactivated channels into drug-bound, slow-inactivated channels.
Methyl eugenol is a potential candidate as an effective local anesthetic and analgesic. The antinociceptive and anesthetic effects of methyl eugenol result from the inhibitory action of methyl eugenol on peripheral Na(+) channels.
甲基丁香酚是从中药细辛中提取的主要活性成分，已被用于治疗牙痛及其他疼痛。以往的体内研究表明，甲基丁香酚具有麻醉和镇痛作用。本研究旨在确定其对神经系统疾病作用的潜在机制。
利用转染了Nav1.7的CHO细胞的电生理记录，探索并表征甲基丁香酚与Na(+)通道的直接相互作用。
在全细胞膜片钳模式下，甲基丁香酚以浓度和电压依赖性方式持续抑制外周神经Nav1.7电流，在-100 mV钳制电位下IC50为295 μmol/L。在功能上，甲基丁香酚优先结合处于失活和/或开放状态的Nav1.7通道，与处于静息状态的通道结合较弱。因此，在甲基丁香酚存在的情况下，与未处理的通道相比，Nav1.7通道在稳态失活实验中表现出激活可用性降低、强烈的使用依赖性抑制、结合动力学增强以及失活后恢复缓慢。对甲基丁香酚与通道静息态和失活态亲和力的估计也表明，甲基丁香酚优先结合失活通道，与静息态通道相比亲和力高6.4倍。在较高浓度的甲基丁香酚下，失活通道未能完全恢复到对照水平，这意味着该药物可能会使更多药物结合的快速失活通道转变为药物结合的缓慢失活通道。
甲基丁香酚是一种有潜力的有效局部麻醉剂和镇痛药候选物。甲基丁香酚的镇痛和麻醉作用源于其对外周Na(+)通道的抑制作用。
