Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 12 Smętna Street, 31-343 Kraków, Poland.
Pharmacol Biochem Behav. 2022 Sep;219:173452. doi: 10.1016/j.pbb.2022.173452. Epub 2022 Aug 27.
There is still no effective treatment for central nervous system (CNS) pathologies, including cerebral ischemia, neurotrauma, and neurodegenerative diseases in which the Glu/GABA balance is disturbed with associated excitotoxicity. It is thus important to search for new efficacious therapeutic strategies. Preclinical studies on the role of metabotropic glutamate receptors (mGluRs) in neuroprotection conducted over the years show that these receptors may have therapeutic potential in these CNS disorders. However, clinical trials, especially for treating Parkinson's disease, have been unsatisfactory. This review focuses on the specific role of group III mGluRs in neuroprotection in experimental in vitro and in vivo models of excitotoxicity/neurotoxicity using neurotoxins as well as ischemia, traumatic brain injury, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's diseases, and multiple sclerosis. The review highlights recent preclinical studies in which group III mGluR ligands (especially those acting at mGluR4 or mGluR7) were administered after damage, thus emphasizing the importance of the therapeutic time window in the treatment of ischemic stroke and traumatic brain injury. From a clinical standpoint, the review also highlights studies using group III mGluR agonists with favorable neuroprotective efficacy (histological and functional) in experimental ischemic stroke, including healthy normotensive and-hypertensive rats. This review also summarizes possible mechanisms underlying the neuroprotective activity of the group III mGluR ligands, which may be helpful in developing more effective and safe therapeutic strategies. Therefore, to fully assess the role of these receptors in neuroprotection, it is necessary to uncover new selective ligands, primarily those stimulating mGlu4 and mGlu7 receptors.
目前，针对包括脑缺血、神经创伤和神经退行性疾病在内的中枢神经系统（CNS）病变，仍没有有效的治疗方法，这些疾病都存在谷氨酸/GABA 平衡紊乱伴兴奋性毒性。因此，寻找新的有效治疗策略非常重要。多年来，有关代谢型谷氨酸受体（mGluRs）在神经保护作用的临床前研究表明，这些受体可能在这些 CNS 疾病中具有治疗潜力。然而，临床试验，特别是针对治疗帕金森病的临床试验，结果并不理想。本综述重点介绍了使用神经毒素以及缺血、创伤性脑损伤和神经退行性疾病（如帕金森病、阿尔茨海默病和多发性硬化症）的体外和体内兴奋毒性/神经毒性模型中，mGluR3 亚类在神经保护中的特定作用。该综述强调了最近的临床前研究，即在损伤后给予 mGluR3 配体（特别是作用于 mGluR4 或 mGluR7 的配体），从而强调了在治疗缺血性中风和创伤性脑损伤时治疗时间窗的重要性。从临床角度来看，该综述还强调了在实验性缺血性中风中使用具有良好神经保护作用（组织学和功能）的 mGluR3 激动剂的研究，包括健康的正常血压和高血压大鼠。该综述还总结了 mGluR3 配体神经保护活性的可能机制，这可能有助于开发更有效和安全的治疗策略。因此，为了充分评估这些受体在神经保护中的作用，有必要揭示新的选择性配体，主要是那些能刺激 mGlu4 和 mGlu7 受体的配体。
