The purpose of the present study was to examine the protective action and mechanisms of quercetin on the blood-brain barrier (BBB) in rats subjected to transient middle cerebral artery occlusion (tMCAO) and reperfusion. Quercetin (10, 30, 50 mg/kg) was intraperitoneally administered at the onset of reperfusion. The results showed that quercetin significantly reduced cerebral infarct volume, neurological deficit, BBB permeability and ROS generation via Sirt1/Nrf2/HO-1 signaling pathway. Moreover, EX527, a selective inhibitor of Sirt1, reversed these neuroprotective effects. Our findings indicate that quercetin has neuroprotective effects against cerebral ischemia-reperfusion injury by protecting BBB through Sirt1 signaling pathway in MCAO rats. Graphical Abstract

Salvianolic acid A (SalA) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box O3a (FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of SalA on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of SalA, SH-SY5Y cells and Sprague-Dawley rats were applied, which were exposed to oxygen glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/reperfusion (MCAO/R) injuries, respectively. The involved pathway was identified using the specific inhibitor LY294002. Results showed that SalA concentration-dependently inhibited OGD/R injury triggered cell viability loss. SalA reduced cerebral infarction, lowered brain edema, improved neurological function, and inhibited neuron apoptosis in MCAO/R rats, which were attenuated by the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) specific inhibitor LY294002. SalA time- and concentration-dependently upregulated the phosphorylation levels of protein kinase B (AKT) and its downstream protein FOXO3a. Moreover, the nuclear translocation of FOXO3a was inhibited by SalA both in vivo and in vitro, which was also reversed by LY294002. The above results indicated that SalA fought against ischemia/reperfusion damage at least partially via the AKT/FOXO3a/BIM pathway.