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

Abstract

AbstractIschemia–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.