Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Neuropharmacology. 2018 Dec;143:38-48. doi: 10.1016/j.neuropharm.2018.09.021. Epub 2018 Sep 14.
Riluzole is a potent neuroprotective agent which primarily inhibits excitatory neurotransmission interfering with presynaptic release, uptake and postsynaptic actions of glutamate by mechanisms that are not well understood. Riluzole and related prodrugs with improved blood brain barrier penetrance, are shown to be effective for the treatment of amyotrophic lateral sclerosis, ataxias, epilepsy and mood disorders. Our study was undertaken to decipher molecular and subcellular mechanisms of riluzole's antiglutamatergic effect, particularly focusing on presynaptic active zone structure and function. Applying multifarious live cell imaging techniques and amperometric glutamate recordings, we measured the impact of riluzole on presynaptic activity, synaptic vesicle recycling and glutamate release. Our in vitro and in vivo data revealed a unique mechanism whereby riluzole reduces the efficacy of glutamatergic transmission by selectively lowering the size of the readily releasable pool. This effect was correlated with the inhibition of protein kinase C-dependent Munc18-1 phosphorylation which is known to interfere with neurotransmitter release.
利鲁唑是一种有效的神经保护剂，主要通过尚未完全阐明的机制抑制兴奋性神经递质传递，干扰谷氨酸的突触前释放、摄取和突触后作用。利鲁唑及其相关前药具有改善血脑屏障通透性，已被证明对肌萎缩侧索硬化症、共济失调、癫痫和情绪障碍的治疗有效。我们的研究旨在破译利鲁唑的抗谷氨酸作用的分子和亚细胞机制，特别是重点关注突触前活性区的结构和功能。应用多种活细胞成像技术和安培法谷氨酸记录，我们测量了利鲁唑对突触前活动、突触囊泡再循环和谷氨酸释放的影响。我们的体外和体内数据揭示了一种独特的机制，即利鲁唑通过选择性降低易释放池的大小来降低谷氨酸能传递的效率。这种效应与蛋白激酶 C 依赖性 Munc18-1 磷酸化的抑制相关，已知该磷酸化会干扰神经递质释放。
