Xuming Zhusan Decoction Attenuates Post‐Stroke via Modulating TLR4/MYD88/NF‐κB Pathway in Mice

Ischemic stroke induces neuroinflammation that exacerbates neuronal damage. The Chinese Medicine Xuming Zhusan (XMZS) has shown promising efficacy in stroke treatment, but its mechanisms are unclear. This study aimed to explore the effect of XMZS on microglial‐mediated neuroinflammation and explore its molecular targets. In vivo experiments were conducted using a mouse model of cerebral ischemia–reperfusion injury induced by middle cerebral artery occlusion (MCAO), and in vitro studies were performed on primary microglia and cortical neurons with Oxygen–Glucose Deprivation/Reoxygenation (OGD/R) models. Behavioral assessments, histological analyses, Western blotting, co‐immunoprecipitation, confocal microscopy, and enzyme‐linked immunosorbent assay (ELISA) were employed to evaluate the neuroprotective effects of XMZS and its regulatory role in the TLR4/MYD88/NF‐κB pathway. Results showed that high‐dose (63 g/kg) XMZS improved neurological and cognitive functions, reduced infarct volume and brain edema in MCAO mice. Mechanistically, XMZS suppressed microglial activation, decreased the levels of pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α), and downregulated the expression of TLR4, MYD88, and phosphorylated p65 in the TLR4/MYD88/NF‐κB pathway. Additionally, cinditioned medium from XMZS‐treated microglia enhanced the viability of primary neurons. In conclusion, XMZS exerts neuroprotective effects against cerebral ischemia–reperfusion injury by modulating the TLR4/MYD88/NF‐κB pathway, thereby attenuating microglia‐mediated neuroinflammation.