xav939 and Brain-Ischemia

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.. 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).. 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.. This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.

Topics: Animals; Apoptosis; bcl-X Protein; beta Catenin; Brain; Brain Ischemia; Caspase 3; Cyclin D1; Ginkgolides; Glycogen Synthase Kinase 3 beta; Heterocyclic Compounds, 3-Ring; Infarction, Middle Cerebral Artery; Lactones; Male; Mice; Nerve Growth Factor; Neurogenesis; Recovery of Function; Stroke; Up-Regulation; Wnt Signaling Pathway

White matter tracts are composed of axons and myelinating oligodendrocytes. Oligodendrocytes are the myelinating cells in the central nervous system that allow formation of myelin and saltatory nerve conduction. Cerebral white matter is highly vulnerable to ischemic injury in adults and neonates. White matter injury in newborn brains results in cerebral palsy and cognitive disability. In this study, we found that XAV939, a small-molecular inhibitor that stimulated β-catenin degradation by stabilizing axin, protected against serum and glucose deprivation (SGD)-induced cell death in oligodentrocyte cell line OLN-93 cells in a concentration-dependent manner. We further showed that XAV939 reduced caspase-3 and caspase-8 levels and increased the expression of phosphorylated Akt in SGD-induced OLN-93 cells. Our data demonstrate that XAV939 protects against neonatal hypoxic/ischemic injury. In summary, our results demonstrate that XAV939 confers neuroprotection against SGD-induced injury in OLN-93 cells via its antiapoptotic activity and the loss of oligodendrocytes and neurons in neonatal hypoxic/ischemic injury.

Topics: Animals; Animals, Newborn; Apoptosis; beta Catenin; Brain Infarction; Brain Ischemia; Caspases; Cell Line, Transformed; Cells, Cultured; Chromones; Disease Models, Animal; Enzyme Inhibitors; Heterocyclic Compounds, 3-Ring; Morpholines; Neurons; Neuroprotective Agents; Oligodendroglia; Rats; Rats, Sprague-Dawley; Serum; Time Factors