Icaritin alleviates cerebral ischemia-reperfusion injury by regulating NMDA receptors through ERK signaling

N-methyl-D-aspartate (NMDA) receptors are key signaling molecules that mediate excitotoxicity during cerebral ischemia. GluN2A-containing NMDA receptors, which are mostly located in the intrasynaptic region, mediate normal physiological processes and promote neuronal survival. GluN2B-containing NMDA receptors, which are mostly located in the extrasynaptic region, mediate excitotoxicity injury and promote neuronal death during ischemia. This study investigated the ability of icaritin (ICT) to protect against cerebral ischemia-reperfusion injury (CI/RI) by regulating GluN2B-containing NMDA receptors through extracellular signaling regulatory ki-nases/death associated protein kinase 1 (ERK/DAPK1) signaling. A rat CI/RI model was established by transient middle cerebral artery occlusion (tMCAO). Following treatment with ICT and the ERK-specific inhibitor U0126, cerebral infarction, neurological function, and excitotoxicity-related molecule expression were assessed 24 h after reperfusion. ICT treatment significantly decreased cerebral infarct volume, improved neurological function, and regulated NMDA receptor subtype expression and ERK/DAPK1 signaling activation. The ability of ICT to increase GluN2A and postsynaptic density protein 95 (PSD95) mRNA and protein expression, inhibit GluN2B expression, and regulate DAPK1 activation was reversed after administration of the ERK-specific inhibitor U0126. These data indicated that ICT inhibited excitotoxicity injury and exerted a protective effect against CI/RI that was likely mediated by increased ERK signaling pathway activation and regulation of extrasynaptic and intrasynaptic NMDA receptor function, providing a new therapeutic target for ischemic encephalopathy.