Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; Clinical Medical School, Beijing University of Traditional Chinese Medicine, Beijing 100029, China.
Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
Biomed Pharmacother. 2022 Jul;151:113125. doi: 10.1016/j.biopha.2022.113125. Epub 2022 May 24.
Glutamate-mediated excitotoxicity is an important mechanism leading to post ischemic stroke damage. After acute stroke, the sudden reduction in cerebral blood flow is most initially followed by ion transport protein dysfunction and disruption of ion homeostasis, which in turn leads to impaired glutamate release, reuptake, and excessive N-methyl-D-aspartate receptor (NMDAR) activation, promoting neuronal death. Despite extensive evidence from preclinical studies suggesting that excessive NMDAR stimulation during ischemic stroke is a central step in post-stroke damage, NMDAR blockers have failed to translate into clinical stroke treatment. Current treatment options for stroke are very limited, and there is therefore a great need to develop new targets for neuroprotective therapeutic agents in ischemic stroke to extend the therapeutic time window. In this review, we highlight recent findings on glutamate release, reuptake mechanisms, NMDAR and its downstream cellular signaling pathways in post-ischemic stroke damage, and review the pathological changes in each link to help develop viable new therapeutic targets. We then also summarize potential neuroprotective drugs and therapeutic approaches for these new targets in the treatment of ischemic stroke.
谷氨酸介导的兴奋性毒性是导致缺血性中风后损伤的重要机制。急性中风后，脑血流的突然减少最初会导致离子转运蛋白功能障碍和离子平衡破坏，进而导致谷氨酸释放、再摄取受损和过度 N-甲基-D-天冬氨酸受体 (NMDAR) 激活，促进神经元死亡。尽管大量临床前研究证据表明，缺血性中风期间过度的 NMDAR 刺激是中风后损伤的关键步骤，但 NMDAR 阻滞剂未能转化为中风的临床治疗。目前中风的治疗选择非常有限，因此非常有必要为缺血性中风中的神经保护治疗剂开发新的靶点，以延长治疗时间窗。在这篇综述中，我们重点介绍了谷氨酸释放、再摄取机制、NMDAR 及其下游细胞信号通路在缺血性中风损伤中的最新发现，并综述了每个环节的病理变化，以帮助开发可行的新治疗靶点。然后，我们还总结了这些新靶点在缺血性中风治疗中潜在的神经保护药物和治疗方法。
