Polydatin Inhibits Neuroinflammation in Cerebral Ischemia–Reperfusion Injury Through Suppressing the CXCL3 / CXCR2 Axis

ABSTRACT Aim The aim of this study is to investigate the precise mechanisms by which Polydatin (PD) ameliorates cerebral ischemia–reperfusion injury (CIRI). Methods We first established a rat model of CIRI to evaluate PD's therapeutic effects. Transcriptomic analysis was used to explore PD's impact on gene expression in ischemic brain tissue of CIRI rats. OGD/R‐induced microglial activation experiments validated that PD inhibits microglial activation by targeting the CXCL3/CXCR2 axis. Results PD intervention improved neurological function scores of CIRI rats, reduced infarct area, alleviated pathological damage, and preserved Nissl bodies in brain tissue. It also modulated oxidative stress levels. Transcriptomic analysis showed enrichment of the Cytokine–cytokine receptor interaction pathway and several inflammatory pathways after PD intervention, with downregulation of CXCL3 and CXCR2. PD decreased pro‐inflammatory cytokine levels and CXCL3/CXCR2 protein expression in ischemic brain tissue of CIRI rats, and reduced positive expression areas of IBA1 + CXCL3 + , IBA1 + CXCR2 + , and MPO + CXCR2 + . In vitro experiments demonstrated that PD reduced pro‐inflammatory cytokine levels in BV2 cell supernatants treated with OGD/R and inhibited BV2 cell migration. However, these effects were abolished when treated with CXCL3 neutralizing antibody and SiCXCR2. Conclusion Our findings suggest that PD can inhibit microglial migration and activation by acting on the CXCL3/CXCR2 axis, thereby alleviating the inflammatory response in CIRI.