Background: This study aims to investigate the protective effect of quercetin against global cerebral ischemia‒reperfusion (GCI/R) injury in rats and elucidate the underlying mechanism.
Methods: A GCI/R injury rat model was established using a four-vessel occlusion (4-VO) method. An oxygen–glucose deprivation/reoxygenation (OGD/R) injury model was induced in BV2 cells. The extent of injury was assessed by evaluating neurological deficit scores (NDS) and brain water content and conducting behavioral tests. Pathomorphological changes in the prefrontal cortex were examined. Additionally, the study measured the levels of inflammatory cytokines, the degree of microglial activation and polarization, and the protein expression of Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor inducing interferon-β (TRIF).
Results: Quercetin pretreatment significantly ameliorated neurological impairment, improved learning and memory abilities, and reduced anxiety in rats subjected to GCI/R injury. Furthermore, quercetin administration effectively mitigated neuronal injury and brain edema. Notably, it suppressed microglial activation and hindered polarization toward the M1 phenotype. Simultaneously, quercetin downregulated the expression of TLR4 and TRIF proteins and attenuated the release of IL-1β and TNF-α.
Conclusion: This study highlights the novel therapeutic potential of quercetin in alleviating GCI/R injury. Quercetin demonstrates its neuroprotective effects by inhibiting neuroinflammation and microglial activation while impeding their transformation into the M1 phenotype through modulation of the TLR4/TRIF pathway.

Keywords: quercetin, cerebral ischemia, neuroprotection, neuroinflammation