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Cycloastragenol (CAG) is the active form of astragaloside Ⅳ isolated from Astragalus Radix,which displays multiple pharmacological effects.Silent information regulator 1 (SIRT1),a class Ⅲ histone deacetylase,has been shown to play an important role in neuroprotection against cerebral ischemia.In this study,we investigated whether CAG protected against ischemic brain injury and,if so,whether the beneficial effects were associated with the regulation of SIRT1 in the ischemic brain.Mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) followed by repeffusion.CAG (5,10,20 mg/kg) was injected intraperitoneally at the onset of reperfusion,12 h later and then twice daily for up to three days.CAG dose-dependently reduced brain infarct volume,significantly ameliorated functional deficits,and prevented neuronal cell loss in MCAO mice.Meanwhile,CAG significantly reduced matrix metalloproteinase-9 activity,prevented tight junction degradation and subsequently ameliorated blood-brain barrier disruption.Moreover,CAG significantly upregulated SIRT1 expression in the ischemic brain but did not directly activate its enzymatic activity.Concomitant with SIRT1 upregulation,CAG reduced p53 acetylation and the ratio of Bax to Bcl-2 in the ischemic brain.CAG also inhibited NF-κB p65 nuclear translocation.As a result,CAG suppressed the mRNA expression of pro-inflammatory cytokines,including TNF-α and IL-1β,and inhibited the activation of microglia and astrocytes in the ischemic brain.Our findings suggest that CAG is neuroprotective against ischemic brain injury in mice and that its beneficial effect may involve SIRT1 upregulation and the inhibition of apoptosis and neuroinflammation in the ischemic brain.