Kwan Cynthia, Kang Woojin, Kim Esther, Belliveau Sébastien, Frouni Imane, Huot Philippe
Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada.
Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada.
Int Rev Neurobiol. 2023;168:1-31. doi: 10.1016/bs.irn.2022.10.001. Epub 2022 Nov 11.
Parkinson's disease (PD) is a complex disorder that leads to alterations in multiple neurotransmitter systems, notably glutamate. As such, several drugs acting at glutamatergic receptors have been assessed to alleviate the manifestation of PD and treatment-related complications, culminating with the approval of the N-methyl-d-aspartate (NMDA) antagonist amantadine for l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. Glutamate elicits its actions through several ionotropic and metabotropic (mGlu) receptors. There are 8 sub-types of mGlu receptors, with sub-types 4 (mGlu) and 5 (mGlu) modulators having been tested in the clinic for endpoints pertaining to PD, while sub-types 2 (mGlu) and 3 (mGlu) have been investigated in pre-clinical settings. In this book chapter, we provide an overview of mGlu receptors in PD, with a focus on mGlu, mGlu, mGlu and mGlu receptors. For each sub-type, we review, when applicable, their anatomical localization and possible mechanisms underlying their efficacy for specific disease manifestation or treatment-induced complications. We then summarize the findings of pre-clinical studies and clinical trials with pharmacological agents and discuss the potential strengths and limitations of each target. We conclude by offering some perspectives on the potential use of mGlu modulators in the treatment of PD.
帕金森病（PD）是一种复杂的疾病，会导致多种神经递质系统发生改变，尤其是谷氨酸。因此，人们已对几种作用于谷氨酸能受体的药物进行了评估，以减轻帕金森病的症状和治疗相关并发症，最终N-甲基-D-天冬氨酸（NMDA）拮抗剂金刚烷胺被批准用于治疗左旋多巴（l-DOPA）诱导的运动障碍。谷氨酸通过几种离子型和代谢型（mGlu）受体发挥作用。mGlu受体有8种亚型，其中4型（mGlu4）和5型（mGlu5）调节剂已在临床上针对与帕金森病相关的终点进行了测试，而2型（mGlu2）和3型（mGlu3）则已在临床前研究中进行了调查。在本章中，我们概述了帕金森病中的mGlu受体，重点介绍mGlu4、mGlu5、mGlu2和mGlu3受体。对于每种亚型，我们在适用的情况下回顾其解剖定位以及它们对特定疾病表现或治疗引起的并发症产生疗效的可能机制。然后，我们总结了使用药物进行临床前研究和临床试验的结果，并讨论了每个靶点的潜在优势和局限性。最后，我们对mGlu调节剂在帕金森病治疗中的潜在应用提出了一些观点。
