Dl-3-n-Butylphthalide Promotes Neurogenesis in Ischemic Stroke Mice Through Wnt/β-Catenin Signaling Activation and Neurotrophic Factor Production

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 aimed to determine whether and how NBP promotes neurogenesis in cerebral ischemic injury. Adult C57BL/6 mice, subjected to distal middle cerebral artery occlusion (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 the Wnt/β-catenin signaling pathway and the expression of neurotrophic factors were detected by western blotting and qRT-PCR. Administration of NBP reduced infarct volume and ameliorated neurological deficits after stroke. NBP promoted the proliferation of NSCs in the SVZ, migration of neuroblasts along the corpus callosum, and differentiation of neuroblasts toward neurons in the peri-infarct zone, resulting in restored neural function. Moreover, we revealed that NBP-induced neurogenesis was associated with the activation of the 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, depending on Wnt/β-catenin signaling activation and neurotrophic factor production. Thus, NBP may be a promising candidate for delayed treatment of ischemic stroke.