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Cerebral ischemia/reperfusion (I/R) results in harmful consequences during ischemic stroke,especially the disruption of the blood-brain barrier (BBB),which leads to severe hemorrhagic transformation through aggravation of edema and brain hemorrhage.Our previous study demonstrated that icariside Ⅱ (ICS Ⅱ),which is derived from Herba Epimedii,attenuates cerebral I/R injury by inhibiting the GSK-3ββ-mediated activation of autophagy both in vitro and in vivo.However,the effect of ICS Ⅱ on the BBB remains unclear.Thus,in this study,we investigated the regulation of BBB integrity by ICS Ⅱ after cerebral I/R injury and further explored the underlying mechanism in rats.Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO),and the treatment groups were administered ICS Ⅱ at a dose of 16 mg/kg by gavage twice a day for 3 days.The results showed that ICS Ⅱ effectively prevented BBB disruption,as evidenced by Evans Blue staining.Moreover,ICS Ⅱ not only significantly reduced the expression of MMP2/9 but also increased TIMP1 and tight junction protein (occludin,claudin 5,and ZO 1) expression.Intriguingly,ICS Ⅱ may directly bind to both MMP2 and MMP9,as evidenced by molecular docking.In addition,ICS Ⅱ also inhibited cerebral I/R-induced apoptosis and ameliorated the Bax/Bcl-2 ratio and cleaved-caspase 3 level.Collectively,our findings reveal that ICS Ⅱ significantly ameliorates I/R-induced BBB disruption and neuronal apoptosis in MCAO rats by regulating the MMP9/TIMP1 balance and inhibiting the caspase 3-dependent apoptosis pathway.