Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109, Xueyuanxi Road, Wenzhou 325027, Zhejiang, China.
Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109, Xueyuanxi Road, Wenzhou 325027, Zhejiang, China.
Exp Neurol. 2019 Mar;313:60-78. doi: 10.1016/j.expneurol.2018.12.005. Epub 2018 Dec 13.
Dendritic and synaptic plasticity in the penumbra are important processes and are considered to be therapeutic targets of ischemic stroke. Treadmill exercise is known to be a beneficial treatment following stroke. However, its effects and potential mechanism in promoting dendritic and synaptic plasticity remain unknown. We have previously demonstrated that the caveolin-1/VEGF signaling pathway plays a positive role in angiogenesis and neurogenesis. Here, we further investigated the effects of treadmill exercise on promoting dendritic and synaptic plasticity in the penumbra and whether they involve the caveolin-1/VEGF signaling pathway. A middle cerebral artery occlusion (MCAO) animal model was established, and rats were randomly divided into eleven groups. At 2 days after MCAO, rats were subjected to treadmill exercise for 7 or 28 days. Daidzein (a specific inhibitor of caveolin-1, 0.4 mg/kg) was used to confirm the effect of caveolin-1/VEGF signaling on exercise-mediated dendritic and synaptic plasticity. Neurobehavioral performance, tissue morphology and infarct volumes were detected by Modified Neurology Severity Score (mNSS), Hematoxylin-eosin (HE), and Nissl staining, while neural plasticity and its molecular mechanism were examined by Golgi-Cox staining, transmission electron microscopy, western blot analysis and immunofluorescence. We found that treadmill exercise promoted dendritic plasticity in the penumbra, consistent with the significant increase in caveolin-1 and VEGF expression; improved neurological recovery; and reduced infarct volume. In contrast to the positive effects of the treadmill, a caveolin-1 inhibitor abrogated the dendritic and synaptic plasticity. Furthermore, we observed that treadmill exercise-induced improved dendritic and synaptic plasticity were significantly inhibited by the caveolin-1 inhibitor, consistent with the lower expression of caveolin-1 and VEGF, as well as the worse neurobehavioral state. The findings indicate that treadmill exercise ameliorates focal cerebral ischemia/reperfusion-induced neurological deficit by promoting dendritic and synaptic plasticity via upregulating caveolin-1/VEGF signaling pathways.
缺血性中风半影区的树突和突触可塑性是重要的过程，被认为是治疗中风的靶点。跑步机运动已被证实是中风后的一种有益治疗方法。然而，其促进树突和突触可塑性的效果和潜在机制尚不清楚。我们之前已经证明了小窝蛋白-1/VEGF 信号通路在血管生成和神经发生中发挥积极作用。在这里，我们进一步研究了跑步机运动对促进半影区树突和突触可塑性的影响，以及它们是否涉及小窝蛋白-1/VEGF 信号通路。建立了大脑中动脉闭塞 (MCAO) 动物模型，将大鼠随机分为十一个组。MCAO 后 2 天，大鼠进行 7 或 28 天的跑步机运动。大豆苷元（小窝蛋白-1 的特异性抑制剂，0.4mg/kg）用于确认小窝蛋白-1/VEGF 信号对运动介导的树突和突触可塑性的影响。通过改良神经功能缺损评分（mNSS）、苏木精-伊红（HE）和尼氏染色检测神经行为表现、组织形态和梗死体积，而通过高尔基-考克斯染色、透射电镜、western blot 分析和免疫荧光检测神经可塑性及其分子机制。我们发现跑步机运动促进了半影区的树突可塑性，这与小窝蛋白-1 和 VEGF 表达的显著增加一致；改善了神经功能恢复；并减少了梗死体积。与跑步机运动的积极作用相反，小窝蛋白-1 抑制剂消除了树突和突触可塑性。此外，我们观察到跑步机运动诱导的树突和突触可塑性的改善明显受到小窝蛋白-1 抑制剂的抑制，这与小窝蛋白-1 和 VEGF 的表达降低以及神经行为状态恶化一致。这些发现表明，跑步机运动通过上调小窝蛋白-1/VEGF 信号通路，改善局灶性脑缺血再灌注引起的神经功能缺损，从而改善树突和突触可塑性。
