XQ-1H alleviates cerebral ischemia in mice through inhibition of apoptosis and promotion of neurogenesis in a Wnt/β-catenin signaling dependent way
- Life Sci. 2019 Oct 15;235:116844. doi: 10.1016/j.lfs.2019.116844.
- 1. State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
- 2. State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
- 3. State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
- 4. State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
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/β-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 GSK3β, which in turn upregulated Wnt1, β-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 GSK3β/Caspase-3 activity and enhancing the expression of Wnt1/β-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.