Department of Neurology, Hebei General Hospital, Shijiazhuang, China.
Department of Neurology, Hebei General Hospital, Shijiazhuang, China; Department of Neurology, Hebei Medical University, Shijiazhuang, China.
Neurosci Lett. 2021 Nov 20;765:136266. doi: 10.1016/j.neulet.2021.136266. Epub 2021 Sep 24.
DL-3-n-butylphthalide (NBP) has neuroprotective effect on chronic cerebral hypoperfusion animals. Here, we explored the role and underlying mechanism of NBP on autophagy and angiogenesis in rats with vascular dementia (VD). Adult male Sprague-Dawley (SD) rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to establish VD model. These rats were randomly divided into five groups: sham, model, NBP (120 mg/kg), Shh siRNA (50 nM), and NBP + Shh siRNA groups. Our results showed that NBP treatment attenuated memory damage in rats with VD, as demonstrated by Morris water maze tests. Immunofluorescence (IF) assay revealed that NBP induced neuronal process length and neuronal activity in hippocampus, which were reversed by Shh silencing. Furthermore, NBP treatment also reduced the expression of autophagy marker proteins B-cell lymphoma-2 interacting protein 1 (Beclin 1) and microtubule-associated protein 1 light chain 3 (LC3), which were further enhanced by Shh silencing. Meanwhile, NBP promoted the angiogenesis, which was accompanied by upregulated vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-1, and Angiopoietin (Ang) expression in the hippocampus. And Shh siRNA co-treatment blocked the angiogenesis induced by NBP. Altogether, our results established that NBP treatment suppressed autophagy and improved angiogenesis and neurobehavioral recovery in VD rats partly by activating the Shh/Ptch1 signaling pathway.
DL-3-正丁基苯酞（NBP）对慢性脑低灌注动物具有神经保护作用。在这里，我们探讨了 NBP 对血管性痴呆（VD）大鼠自噬和血管生成的作用及其潜在机制。成年雄性 Sprague-Dawley（SD）大鼠接受双侧颈总动脉永久性闭塞（2VO）以建立 VD 模型。这些大鼠被随机分为五组：假手术组、模型组、NBP（120mg/kg）组、Shh siRNA（50nM）组和 NBP+Shh siRNA 组。我们的结果表明，NBP 治疗减轻了 VD 大鼠的记忆损伤，这可以通过 Morris 水迷宫测试来证明。免疫荧光（IF）检测显示，NBP 诱导海马神经元突起长度和神经元活性增加，而 Shh 沉默则逆转了这一作用。此外，NBP 治疗还降低了自噬标志物蛋白 B 细胞淋巴瘤-2 相互作用蛋白 1（Beclin 1）和微管相关蛋白 1 轻链 3（LC3）的表达，而 Shh 沉默进一步增强了这种作用。同时，NBP 促进了血管生成，这伴随着海马中血管内皮生长因子（VEGF）、成纤维细胞生长因子（FGF）-1 和血管生成素（Ang）表达的上调。而 Shh siRNA 共同处理阻断了 NBP 诱导的血管生成。总之，我们的研究结果表明，NBP 治疗通过激活 Shh/Ptch1 信号通路抑制自噬，改善 VD 大鼠的血管生成和神经行为恢复。
