Activation of the Wnt/β-catenin/CYP1B1 pathway alleviates oxidative stress and protects the blood-brain barrier under cerebral ischemia/reperfusion conditions.

Abstract

Abstract JOURNAL/nrgr/04.03/01300535-202407000-00033/figure1/v/2023-11-20T171125Z/r/image-tiff Accumulating evidence suggests that oxidative stress and the Wnt/β-catenin pathway participate in stroke-induced disruption of the blood-brain barrier. However, the potential links between them following ischemic stroke remain largely unknown. The present study found that cerebral ischemia leads to oxidative stress and repression of the Wnt/β-catenin pathway. Meanwhile, Wnt/β-catenin pathway activation by the pharmacological inhibitor, TWS119, relieved oxidative stress, increased the levels of cytochrome P450 1B1 (CYP1B1) and tight junction-associated proteins (zonula occludens-1 [ZO-1], occludin and claudin-5), as well as brain microvascular density in cerebral ischemia rats. Moreover, rat brain microvascular endothelial cells that underwent oxygen glucose deprivation/reoxygenation displayed intense oxidative stress, suppression of the Wnt/β-catenin pathway, aggravated cell apoptosis, downregulated CYP1B1 and tight junction protein levels, and inhibited cell proliferation and migration. Overexpression of β-catenin or knockdown of β-catenin and CYP1B1 genes in rat brain microvascular endothelial cells at least partly ameliorated or exacerbated these effects, respectively. In addition, small interfering RNA-mediated β-catenin silencing decreased CYP1B1 expression, whereas CYP1B1 knockdown did not change the levels of glycogen synthase kinase 3β, Wnt-3a, and β-catenin proteins in rat brain microvascular endothelial cells after oxygen glucose deprivation/reoxygenation. Thus, the data suggest that CYP1B1 can be regulated by Wnt/β-catenin signaling, and activation of the Wnt/β-catenin/CYP1B1 pathway contributes to alleviation of oxidative stress, increased tight junction levels, and protection of the blood-brain barrier against ischemia/hypoxia-induced injury.