Erythropoietin‐derived peptide ARA290 mediates brain tissue protection through the β‐common receptor in mice with cerebral ischemic stroke

Aim To explore the neuroprotective effects of ARA290 and the role of β‐common receptor (βCR) in a mouse model of middle cerebral artery occlusion (MCAO). Methods This study included male C57BL/6J mice that underwent MCAO and reperfusion. The neuroprotective effect of ARA290 on MCAO‐induced brain injury was investigated using neurological function tests (Longa and modified neurological severity score). Cerebral infarction was examined by 2, 3, 5‐triphenyl tetrazolium chloride staining, neuronal apoptosis was assessed by immunofluorescence staining, blood parameters were measured using a flow cytometry‐based automated hematology analyzer, liquid chromatography with tandem mass spectrometry was used to identify the serum metabolomics signature, inflammatory cytokines and liver index were detected by commercially available kits, and the protein levels of the erythropoietin (EPO) receptor and βCR were measured by western blot. Results ARA290 exerted a qualitatively similar neuroprotective effect after MCAO as EPO. ARA290 significantly reduced neuronal apoptosis and the level of inflammatory cytokines in the brain tissue. However, ARA290's neuroprotective effect was significantly suppressed following the injection of siRNA against βCR. Conclusion ARA290 provided a neuroprotective effect via βCR in cerebral ischemic mice without causing erythropoiesis. This study provides novel insights into the role of ARA290 in ischemic stroke intervention. ARA290 exerts a neuroprotective action against cerebral ischemic injury by suppressing neuronal apoptosis and inflammatory reactions in mice without motivating splenomegaly and erythropoiesis via the EPO receptor monomer and β‐common receptor.