Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke

• Published in: Biomedicine & pharmacotherapy Vol. 151; p. 113125
• Main Authors: Shen, Zihuan, Xiang, Mi, Chen, Chen, Ding, Fan, Wang, Yuling, Shang, Chang, Xin, Laiyun, Zhang, Yang, Cui, Xiangning
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.07.2022; Elsevier
• Subjects: Excitotoxicity; Glutamate; Ischemic stroke; Neuroprotection; NMDA receptor; BBB; CaMK; HDACs; EPO; OXM; JNK; PDCD6; ARMS; AQP4; GDH; Ischemic stroke; E2; MetAP2; GLS; NF-κB; PI3K; mTOR; FGF-21; AIF; AA; PSD; FOXO; NKA; SUR1; PKA; TubA; PKD; PLA2; IGF-1; CIP; MAPK; Glutamate; CAM; LRRC8A, SWELL1; OAA; AP; Kidins220; NR2B; AAT; nNOS; NR2A; AMPK; NMDAR; ERK; lncRNAs; Neuroprotection; NCX; COX-2; miRNAs; CNS; NDC; XC- system; CPPs; GSK-3β; MAGUK; CREB; GRK2; Stat; ceRNAs; PDH; α-KG; TGF-α; TRPM4; PGE2; DRSAb; GLP-1; BDNF; DAPKs; TCA cycle; Pyr; SNAT; STEP; GS; EAAT; GFAP; PC; CDK5; Jak; tDCS; CRMP2; KuA; PF; VRAC; Excitotoxicity; PAG; MDM2; MPTP; NMDA receptor; IPC; rTMS; MCU; GLC
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.113125

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. [Display omitted] •Glutamate-mediated excitotoxicity is an important mechanism leading to postischemic stroke injury and a potential therapeutic target for ischemic stroke.•Summarize recent findings regarding the pathological changes and mechanisms of glutamate excitotoxicity in post-ischemic stroke injury.•Discuss the role of glutamate excitotoxicity in ischemic stroke, summarize and provide targets in intervening the pathological mechanisms of glutamate excitotoxicity, with a focus on summarizing new developable therapeutic targets in glutamate release, reuptake mechanisms, NMDAR and its downstream cellular signaling pathways, provide potential neuroprotective drugs and therapeutic approaches for the treatment of ischemic stroke.