School of Biomedical Sciences, University of Queensland, Brisbane, Qld. 4072, Australia.
CNS Neurosci Ther. 2011 Feb;17(1):4-31. doi: 10.1111/j.1755-5949.2009.00116.x.
Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of adults which preferentially attacks the neuromotor system. Riluzole has been used as the only approved treatment for amyotrophic lateral sclerosis since 1995, but its mechanism(s) of action in slowing the progression of this disease remain obscure. Searching PubMed for "riluzole" found 705 articles published between January 1996 and June 2009. A systematic review of this literature found that riluzole had a wide range of effects on factors influencing neural activity in general, and the neuromotor system in particular. These effects occurred over a large dose range (<1 μM to >1 mM). Reported neural effects of riluzole included (in approximate ascending order of dose range): inhibition of persistent Na(+) current = inhibition of repetitive firing < potentiation of calcium-dependent K(+) current < inhibition of neurotransmitter release < inhibition of fast Na(+) current < inhibition of voltage-gated Ca(2+) current = promotion of neuronal survival or growth factors < inhibition of voltage-gated K(+) current = modulation of two-pore K(+) current = modulation of ligand-gated neurotransmitter receptors = potentiation of glutamate transporters. Only the first four of these effects commonly occurred at clinically relevant concentrations of riluzole (plasma levels of 1-2 μM with three- to four-fold higher concentrations in brain tissue). Treatment of human ALS patients or transgenic rodent models of ALS with riluzole most commonly produced a modest but significant extension of lifespan. Riluzole treatment was well tolerated in humans and animals. In animals, despite in vitro evidence that riluzole may inhibit rhythmic motor behaviors, in vivo administration of riluzole produced relatively minor effects on normal respiration parameters, but inhibited hypoxia-induced gasping. This effect may have implications for the management of hypoventilation and sleep-disordered breathing during end-stage ALS in humans.
肌萎缩侧索硬化症（ALS）是一种成人致命性的神经退行性疾病，主要影响运动神经系统。自 1995 年以来，利鲁唑一直被用作治疗肌萎缩侧索硬化症的唯一批准药物，但它减缓疾病进展的作用机制仍不清楚。在 PubMed 中搜索“利鲁唑”，发现 1996 年 1 月至 2009 年 6 月期间发表了 705 篇文章。对这些文献的系统回顾发现，利鲁唑对一般影响神经活动的因素以及特别是运动神经系统有广泛的影响。这些作用发生在一个较大的剂量范围内（<1 μM 至>1 mM）。报告的利鲁唑的神经作用包括（按剂量范围从高到低的大致顺序排列）：持续钠电流抑制=重复放电抑制<钙依赖性钾电流增强<神经递质释放抑制<快速钠电流抑制<电压门控钙电流抑制=神经元存活或生长因子促进<电压门控钾电流抑制=双孔钾电流调制=配体门控神经递质受体调制=谷氨酸转运体增强。只有前四种作用通常发生在利鲁唑的临床相关浓度（血浆浓度为 1-2 μM，脑组织中的浓度高出三到四倍）。用利鲁唑治疗人类肌萎缩侧索硬化症患者或肌萎缩侧索硬化症转基因啮齿动物模型最常见的是适度但显著延长了寿命。利鲁唑在人和动物中耐受性良好。在动物中，尽管有体外证据表明利鲁唑可能抑制节律性运动行为，但体内给予利鲁唑对正常呼吸参数的影响相对较小，但抑制了缺氧引起的喘息。这一效应可能对人类肌萎缩侧索硬化症终末期低通气和睡眠呼吸障碍的管理具有重要意义。
