Dl-3-n-butylphthalide promotes neurogenesis in ischemic stroke mice through Wnt/β- catenin signaling activation and neurotrophic factors production

Abstract Synchronized neurogenesis and angiogenesis after stroke have been well documented, and inducing neurovascular remodeling may provide a promising strategy to promote tissue repair and functional recovery. Dl-3-n-butylphthalide (NBP) was reported to exert a potent angiogenic activity in rodent models of stroke. However, little is currently known regarding the effects and mechanisms of NBP on neurogenesis in ischemic stroke. This study was to determine whether and how NBP promoted neurogenesis in cerebral ischemic injury. Adult C57BL/6 mice, subjected to occlusion of distal branches of middle cerebral artery (dMCAO), were treated with NBP. The efficacy of NBP was assessed using neurologic deficits and infarct volume. Immunofluorescent staining was applied to evaluate neurogenesis. The regulation of Wnt/β-catenin signaling pathway and neurotrophic factors were detected by western blotting and qRT-PCR. Administration of NBP reduced infarct volume and ameliorated neurological deficits after stroke. NBP promoted proliferation of NSCs in the SVZ, migration of neuroblasts along the corpus callosum, and differentiation of neuroblasts towards neurons in the peri-infarct zone, resulting in restored neural function. Moreover, we revealed that NBP-induced neurogenesis was associated with the activation of Wnt/β-catenin pathway, which was reversed by DKK1. In addition, NBP increased the production of VEGF and BDNF. Our data have unveiled the potentials of NBP to promote neurogenesis and neural functional recovery after stroke, dependent on Wnt/β-catenin signaling activation and neurotrophic factors production. Thus, NBP may be a promising candidate for delayed treatment of ischemic stroke.