XQ-1H regulates Wnt/GSK3β/β-catenin pathway and ameliorates the integrity of blood brain barrier in mice with acute ischemic stroke

Sep 11, 2020Brain research bulletin

XQ-1H improves blood-brain barrier strength by controlling a key cell signaling pathway in mice with sudden stroke

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Abstract

Treatment with XQ-1H significantly improved neurological behavior and reduced brain infarction volume in a mouse model of cerebral ischemia/reperfusion injury.

XQ-1H reduced brain edema and diminished disruption of the blood-brain barrier in vivo.
In vitro, XQ-1H increased cell viability and preserved the barrier function of brain endothelial cells under stress conditions.
The protective effects of XQ-1H were linked to the activation of the Wnt/GSK3β/β-catenin signaling pathway.
Upregulation of tight junction proteins was observed alongside the protective effects of XQ-1H.
Inhibition of the Wnt/GSK3β/β-catenin pathway diminished the protective effects of XQ-1H.

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10-O-(N, N-dimethylaminoethyl) ginkgolide B methanesulfonate (XQ-1H), a novel analog of ginkgolide B, has been preliminarily recognized to show bioactivities against ischemia-induced injury. However, the underlying mechanism still remains to be fully elucidated. The aim of this study was to investigate the effect of XQ-1H against cerebral ischemia/reperfusion injury (CIRI) from the perspective of blood brain barrier (BBB) protection, and explore whether the underlying mechanism is associated with Wnt/GSK3β/β-catenin signaling pathway activation. The therapeutic effects of XQ-1H were evaluated in mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and in immortalized mouse cerebral endothelial cells (bEnd.3) challenged by oxygen and glucose deprivation/reoxygenation (OGD/R). Results showed that treatment with XQ-1H improved neurological behavior, reduced brain infarction volume, diminished edema, and attenuated the disruption of BBB in vivo. In vitro, XQ-1H increased cell viability and maintained the barrier function of bEnd.3 monolayer after OGD/R. Moreover, the protection of XQ-1H was accompanied with activation of Wnt/GSK3β/β-catenin pathway and upregulation of tight junction proteins. Notably, the protection of XQ-1H was abolished by Wnt/GSK3β/β-catenin inhibitor XAV939 or β-catenin siRNA, indicating XQ-1H exerted protection in a Wnt/GSK3β/β-catenin dependent profile. In summary, XQ-1H attenuated brain injury and maintained BBB integrity after CIRI, and the possible underlying mechanism may be related to the activation of Wnt/GSK3β/β-catenin pathway and upregulation of tight junction proteins.

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