Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
J Physiol. 2012 May 15;590(10):2519-28. doi: 10.1113/jphysiol.2012.230201. Epub 2012 Mar 19.
Riluzole, the only drug available against amyotrophic lateral sclerosis (ALS), has recently been shown to block muscle ACh receptors (AChRs), raising concerns about possible negative side-effects on neuromuscular transmission in treated patients. In this work we studied riluzole's impact on the function of muscle AChRs in vitro and on neuromuscular transmission in ALS patients, using electrophysiological techniques. Human recombinant AChRs composed of α(1)β(1)δ subunits plus the γ or ε subunit (γ- or ε-AChR) were expressed in HEK cells or Xenopus oocytes. In both preparations, riluzole at 0.5 μm, a clinically relevant concentration, reversibly reduced the amplitude and accelerated the decay of ACh-evoked current if applied before coapplication with ACh. The action on γ-AChRs was more potent and faster than on ε-AChRs. In HEK outside-out patches, riluzole-induced block of macroscopic ACh-evoked current gradually developed during the initial milliseconds of ACh presence. Single channel recordings in HEK cells and in human myotubes from ALS patients showed that riluzole prolongs channel closed time, but has no effect on channel conductance and open duration. Finally, compound muscle action potentials (CMAPs) evoked by nerve stimulation in ALS patients remained unaltered after a 1 week suspension of riluzole treatment. These data indicate that riluzole, while apparently safe with regard to synaptic transmission, may affect the function of AChRs expressed in denervated muscle fibres of ALS patients, with biological consequences that remain to be investigated.
利鲁唑是唯一可用于治疗肌萎缩侧索硬化症（ALS）的药物，最近有研究表明它可阻断肌肉乙酰胆碱受体（AChR），这引发了人们对治疗患者神经肌肉传递可能产生负面作用的担忧。在这项工作中，我们使用电生理学技术研究了利鲁唑对体外培养的肌肉 AChR 功能和 ALS 患者神经肌肉传递的影响。在 HEK 细胞或非洲爪蟾卵母细胞中表达由α(1)β(1)δ亚基组成的人重组 AChR，外加γ或ε亚基（γ-或 ε-AChR）。在这两种制剂中，临床相关浓度 0.5 μm 的利鲁唑在与 ACh 共应用之前应用时，可可逆地降低 ACh 诱发电流的幅度并加速其衰减。对γ-AChR 的作用比对ε-AChR 的作用更强、更快。在 HEK 细胞的胞外贴片中，利鲁唑诱导的大电流 ACh 诱发电流阻断在 ACh 存在的最初几毫秒内逐渐发展。在 HEK 细胞和来自 ALS 患者的人肌管中的单通道记录表明，利鲁唑延长了通道关闭时间，但对通道电导和开放时间没有影响。最后，在停止利鲁唑治疗 1 周后，神经刺激诱发的复合肌肉动作电位（CMAPs）在 ALS 患者中保持不变。这些数据表明，利鲁唑虽然在突触传递方面显然是安全的，但可能会影响 ALS 患者失神经纤维表达的 AChR 的功能，其生物学后果仍有待研究。
