Taylor C P, Narasimhan L S
Department of Neurological and Neurodegenerative Diseases, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co. Ann Arbor, Michigan 48105, USA.
Adv Pharmacol. 1997;39:47-98.
Voltage-dependent Na+ channels have long been recognized targets for anti-arrhythmic and local anesthetic drugs. Since the mid-1980s, Na+ channels have become widely accepted as the primary target of anticonvulsants with pharmacological profiles similar to phenytoin, carbamazepine, and lamotrigine. Results from animal models and a few preliminary clinical trials suggest that this class of drugs may also offer significant potential for reducing the neuronal damage caused by ischemic stroke, head trauma, and perhaps certain neurodegenerative diseases. Studies using site-directed mutations of Na+ channels with electrophysiology have provided extensive insight into both the physiology and the interaction of drug molecules with ion channels. This review includes an introduction to Na+ channel structure, molecular biology, and physiology as they relate to pharmacology. A review of several in vitro actions of Na+ channel blockers is provided. Neuroprotective actions with a variety of Na+ channel blockers in models of central nervous system disease in animals and in vitro models are reviewed. Although many voltage-dependent Na+ channel blockers have additional pharmacological targets, the hypothesis that anticonvulsant and neuroprotective actions results from the blockade of Na+ channels is explored.
电压依赖性钠通道长期以来一直被认为是抗心律失常药物和局部麻醉药的作用靶点。自20世纪80年代中期以来，钠通道已被广泛认为是具有与苯妥英、卡马西平和拉莫三嗪相似药理学特征的抗惊厥药物的主要靶点。动物模型和一些初步临床试验的结果表明，这类药物在减轻缺血性中风、头部创伤以及某些神经退行性疾病所致神经元损伤方面可能也具有巨大潜力。利用钠通道定点突变结合电生理学进行的研究，为离子通道的生理学以及药物分子与离子通道的相互作用提供了广泛的见解。本综述包括对与药理学相关的钠通道结构、分子生物学和生理学的介绍。文中还综述了钠通道阻滞剂的几种体外作用。对多种钠通道阻滞剂在动物中枢神经系统疾病模型和体外模型中的神经保护作用进行了综述。尽管许多电压依赖性钠通道阻滞剂还有其他药理学靶点，但本文探讨了抗惊厥和神经保护作用是由钠通道阻滞所致的假说。
