Rosavin protects the blood-brain barrier against ischemia/reperfusion-induced cerebral injury by regulating MAPK-mediated MMPs pathway

Ischemia-reperfusion (I/R) injury is a common pathophysiological condition in ischemic stroke, involving various pathophysiological events, such as inflammation, cytotoxicity, neuronal loss and disruption of the blood-brain barrier (BBB). Rosavin is the major bioactive ingredient of Rhodiola Rosea L. with multiple therapeutic effects. The purpose of this was to investigate the role of rosavin in I/R-induced cerebral injury. A cell oxygen-glucose deprivation and reoxygenation (OGD/R) model and a mouse middle cerebral artery occlusion (MCAO) model were established to induce I/R injury in vitro and in vivo, respectively. MCAO-treated mice and OGD/R-challenged human brain microvascular endothelial cells (HBMVECs) were administrated with or without rosavin at various concentrations. Rosavin-treated mice showed reduced infarct volume, neuronal loss and neuronal cytotoxicity in I/R-injured brains. Rosavin treatment downregulated the expression of pro-inflammatory cytokines, reduced Apoptosis and inhibited the activation of nuclear factor κ B in I/R-injured mice and HBMVECs. Administration with rosavin also alleviated mouse brain oedema and upregulated tight junction proteins in mouse brains after I/R injury, suggesting that rosavin protected mice against I/R-induced BBB disruption. Further analysis revealed that rosavin reduced the BBB permeability in I/R-injured mice and HBMVECs by inhibiting Autophagy. Moreover, rosavin intervention inhibited I/R injury-induced activation of the mitogen-activated protein kinase (MAPK) pathway and upregulation of Matrix Metalloproteinases in both mouse and cell models. In conclusion, rosavin protects the BBB against I/R injury possibly by regulating the MAPK pathway. The above results provide a rationale for further exploration of rosavin as a therapeutic candidate for cerebral I/R injury.

MAPK; MMP; blood-brain barrier; ischemia/reperfusion; ischemic injury; rosavin.