University of Ottawa Brain and Mind Research Institute, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
University of Ottawa Brain and Mind Research Institute, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Pharmacol Ther. 2022 Nov;239:108275. doi: 10.1016/j.pharmthera.2022.108275. Epub 2022 Aug 28.
Glutamate is the primary excitatory neurotransmitter in the brain and plays critical roles in all aspects of neuronal function. Disruption of normal glutamate transmission has been implicated in a variety of neurodegenerative and neuropsychiatric diseases. Glutamate exerts its effect through ionotropic and metabotropic glutamate receptors (mGluRs). mGluR2 and mGluR3 are members of the Group II mGluR family and their activation leads to the inhibition of glutamate release from presynaptic nerve terminals and is also poised upstream of a myriad of signaling pathways in postsynaptic nerve terminals and neuroglia. Therefore, mGluR2 and mGluR3 have been considered as potential drug targets for the treatment of many neurological conditions and several compounds targeting these receptors have been developed. In this review, we discuss what is currently known regarding the contribution of mGluR2 and mGluR3 to the pathophysiology of some neurodegenerative and neuropsychiatric diseases including Amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's diseases, schizophrenia and depression as well as drug addiction. We then highlight the evidence supporting the use of various drugs including orthosteric and allosteric ligands acting on either mGluR2, mGluR3 or both for the management of these brain disorders.
谷氨酸是大脑中主要的兴奋性神经递质，在神经元功能的各个方面都起着关键作用。正常谷氨酸传递的中断与多种神经退行性和神经精神疾病有关。谷氨酸通过离子型和代谢型谷氨酸受体（mGluRs）发挥作用。mGluR2 和 mGluR3 是 II 组 mGluR 家族的成员，它们的激活导致突触前神经末梢释放谷氨酸的抑制，并且还在突触后神经末梢和神经胶质中的众多信号通路的上游处于激活状态。因此，mGluR2 和 mGluR3 被认为是治疗许多神经病症的潜在药物靶点，并且已经开发了几种针对这些受体的化合物。在这篇综述中，我们讨论了目前已知的 mGluR2 和 mGluR3 对一些神经退行性和神经精神疾病的病理生理学的贡献，包括肌萎缩侧索硬化症、阿尔茨海默病、亨廷顿病、帕金森病、精神分裂症和抑郁症以及药物成瘾。然后，我们强调了支持使用各种药物的证据，包括作用于 mGluR2、mGluR3 或两者的正位和别构配体，以治疗这些脑部疾病。
