Journal
LIFE SCIENCES
Volume 235, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2019.116844
Keywords
Ischemic stroke; Apoptosis; Neurogenesis; XQ-1H; Wnt/beta-catenin pathway
Funding
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2016ZX09101031]
- China Pharmaceutical University Double First-Class Construction Technology Innovation Team Project [CPU2018GY23]
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Aims: 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a new derivative of ginkgolide B, has drawn great attention for its potent bioactivities against ischemia-induced injury. The purpose of this study was to further investigate the effect of XQ-1H against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO/R) injuries in mice. Main methods: Treatment of XQ-1H (78 or 39 mg/kg, i.g., bid) 2 h after MCAO improved motor skills and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes and the activation of a pro-apoptotic protein Cleaved-Caspase-3, which in turn induced anti-apoptotic Bcl-xL. Through introducing Wnt/beta-catenin signaling inhibitor XAV-939, XQ-1H was proven to intensively promoted neurogenesis in the peri-infarct cortex, subventricular area (SVZ) and the dentate gyrus (DG) subgranular area (SGZ) in a Wnt signal dependent way by compromising the activation of GSK3 beta, which in turn upregulated Wnt1, beta-catenin, Neuro D1 and Cyclin D1, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Key findings: We conclude that XQ-1H preserved the motor functions, limited apoptosis, and concomitantly promoted neurogenesis-related protein expression by Wnt signaling-dependently compromising GSK3 beta/Caspase3 activity and enhancing the expression of Wnt1/beta-catenin/Neuro D1/Cyclin D1 and Bcl-xL. Significance: This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.
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