Notch信号通路对大鼠脑缺血后神经再生的调控及辛伐他汀与神经再生关系的实验研究
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摘要
缺血性脑血管病(cerebral vascular disease,CVD)严重危害人类健康,它主要的病理损害为局部血液循环障碍和神经元缺失,因此,血供的再恢复和神经修复是缺血性脑损伤临床治疗的两个关键环节。虽然超早期溶栓治疗和急性期神经元保护方面的研究取得了重大进展,但对于大多数患者而言,神经元的死亡不可避免,如何积极有效地促进恢复期神经功能的修复,仍是目前脑缺血研究的热点。
传统观念认为,成年哺乳动物中枢神经系统不可再生,神经元的损伤和神经功能的丧失难以修复,神经功能的重建几乎不可能。上世纪90年代,成年脑内神经干细胞(neural stem cells,NSCs)的发现,改变了这一观念,为脑损伤的治疗提供了新的思路和策略。已有研究发现,实验性脑缺血可诱导侧脑室的脑室下区(subventricular zone,SVZ)和海马齿状回颗粒下层(subgranular zone,SGZ)的内源性NSCs,使其增殖、分化。但由于NSCs数量上的不足及其向神经元分化的比例较少,致使脑缺血后的神经再生难以有效替代神经元的缺失。明确脑缺血后神经再生的机制,通过干预手段促进神经再生,将给脑缺血的治疗带来新的希望。
Notch信号通路是调节细胞增殖、分化的一条重要途径,主要介导细胞的分化抑制信号,许多研究显示,中枢神经系统中Notch信号通路的作用为保持NSCs的增殖状态,抑制神经细胞的分化,阻断Notch信号通路后,神经细胞分化增强。研究Notch信号通路对脑缺血后NSCs的增殖、分化的作用机制,进一步通过干预这一机制促进神经再生,可望为脑缺血治疗提供新的思路。
辛伐他汀作为一种降血脂药物,通过抑制胆固醇合成降低心、脑血管疾病的发病率和死亡率。除降血脂作用外,还可降低血管炎症反应、抑制血小板聚集和血栓形成,称为多效性,这些作用可减少血管的继发性损伤。已有实验证实,用他汀类药物治疗脑出血大鼠,可增强神经再生、突触形成和血管再生,改善神经功能恢复,改善预后。有人证实,辛伐他汀对卒中后血管再生的促进作用是通过影响Notch信号活性实现的。
本实验采用线栓法制备大鼠MCAO模型,以Morris水迷宫检测学习、记忆能力;利用免疫组织化学和免疫荧光化学方法研究脑缺血后内源性NSCs增殖、分化的变化特点,揭示大鼠脑缺血后自体NSCs动员的变化规律;Western-Blot法检测Notch1蛋白表达的动态变化,以DAPT为Notch信号通路阻断剂,观察Notch信号通路对脑缺血后神经再生的调控作用;观察辛伐他汀对脑缺血后神经再生的影响及其与Notch信号的关系,揭示他汀类药物促进神经再生的机制。从行为水平、细胞水平及分子水平研究Notch信号通路及他汀类药物对脑缺血后神经再生的调控机制,为探讨脑缺血的治疗新策略提供实验依据。
Ischemic cerebralvascular disease endangers human health seriously. The prominent pathological hallmark are focal circulation disorder and the loss of neurons. To regain blood supply and repair the neurons are the two key points of clinical treatment. Although the ultra-early arterial thrombolysis is effective, for most patients, neuron death is unavoidable. How to promote functional recovery is still in research. There is evidence that cerebral ischemia can induce the neural stem cells to proliferate and differentiate in the subventricular zone and the subgranular zone. This process is regulated by the Notch signaling. Simvastatin could promote neurogenesis after cerebral ischemia. But the mechanism is less well understood. This study was undertaken to investigate the role of Notch signaling on neurogenesis after cerebral ischemia, to observe the effect of simvastatin on neurogenesis and the relationship between simvastatin and Notch1 hoping to provide a theoretical and experimental foundation for clinical care on ischemic cerebralvascular diseases.
Objective: To observe the dynamic changes of neurogenesis after focal cerebral ischemia in adult rats, to identify the effect of theγ-secretase inhibitor-DAPT on neurogenesis after focal cerebral ischemia and to observe the influence of simvastatin on neurogenesis and the relationship with Notch1. Methods: Total 120 male Wistar rats were randomly divided into the following groups: Sham group, MCAO group, DAPT group and simvastatin group, 6 rats in each group. Rats in experimental groups suffered from focal cerebral ischemia with a nylon suture method. Neurologic impairment was evaluated by Longa five-grade scoring standard. Learning and memory function was tested with Morris water maze. Western-Blot was used to detect Notch1 protein, immunohistochemistry and immunofluorescence for BrdU, BrdU/DCX and BrdU/NeuN expression. The gama-secretase inhibitor-DAPT was used as the blocker of Notch signaling pathway to observe the influence of Notch signaling on neurogenesis after cerebral ischemia. The effect of simvastatin on neurogenesis and its relationship with Notch1 was investigated. Results: (1) From day 3 after ischemia, BrdU and BrdU/DCX double-labeled positive cells began to increase, peaked at day 14, started to decrease at day 21, and more evident at day 28. BrdU/NeuN double-labeled positive cells appeared at day 3 after ischemia, began to increase at day 7, peaked at day 21, then decreased from day 28. (2) After blocking Notch signaling pathway, the escape latency shortened compared with the MCAO group (P<0.05). Notch1 protein expression at different time points was reduced. At each time point the BrdU-positive cells were more than the sham group, but less than the MCAO group (P<0.05). The trend of BrdU/DCX consistented with BrdU. But the BrdU/NeuN double-labeled positive cells were more than the MCAO group at the same time point. (3) The escape latency of simvastatin group was obviously shorter than the MCAO group (P<0.05). Western-Blot result showed significantly decreased expression of Notch1. BrdU, BrdU/DCX and BrdU/NeuN positive cells were more than the same time point of MCAO (P<0.05). Conclusions: (1) Proliferation and differentiation of endogenous neural stem cells can be induced by cerebral ischemia. (2) Notch signaling passway play a key role in ischemia-induced neurogenesis. (3) Simvastatin could promote neurogenesis and functional recovery after cerebral ischemia. The mechanism may be achieved by influencing the activity of Notch signaling.
传统观念认为,成年哺乳动物中枢神经系统不可再生,神经元的损伤和神经功能的丧失难以修复,神经功能的重建几乎不可能。上世纪90年代,成年脑内神经干细胞(neural stem cells,NSCs)的发现,改变了这一观念,为脑损伤的治疗提供了新的思路和策略。已有研究发现,实验性脑缺血可诱导侧脑室的脑室下区(subventricular zone,SVZ)和海马齿状回颗粒下层(subgranular zone,SGZ)的内源性NSCs,使其增殖、分化。但由于NSCs数量上的不足及其向神经元分化的比例较少,致使脑缺血后的神经再生难以有效替代神经元的缺失。明确脑缺血后神经再生的机制,通过干预手段促进神经再生,将给脑缺血的治疗带来新的希望。
Notch信号通路是调节细胞增殖、分化的一条重要途径,主要介导细胞的分化抑制信号,许多研究显示,中枢神经系统中Notch信号通路的作用为保持NSCs的增殖状态,抑制神经细胞的分化,阻断Notch信号通路后,神经细胞分化增强。研究Notch信号通路对脑缺血后NSCs的增殖、分化的作用机制,进一步通过干预这一机制促进神经再生,可望为脑缺血治疗提供新的思路。
辛伐他汀作为一种降血脂药物,通过抑制胆固醇合成降低心、脑血管疾病的发病率和死亡率。除降血脂作用外,还可降低血管炎症反应、抑制血小板聚集和血栓形成,称为多效性,这些作用可减少血管的继发性损伤。已有实验证实,用他汀类药物治疗脑出血大鼠,可增强神经再生、突触形成和血管再生,改善神经功能恢复,改善预后。有人证实,辛伐他汀对卒中后血管再生的促进作用是通过影响Notch信号活性实现的。
本实验采用线栓法制备大鼠MCAO模型,以Morris水迷宫检测学习、记忆能力;利用免疫组织化学和免疫荧光化学方法研究脑缺血后内源性NSCs增殖、分化的变化特点,揭示大鼠脑缺血后自体NSCs动员的变化规律;Western-Blot法检测Notch1蛋白表达的动态变化,以DAPT为Notch信号通路阻断剂,观察Notch信号通路对脑缺血后神经再生的调控作用;观察辛伐他汀对脑缺血后神经再生的影响及其与Notch信号的关系,揭示他汀类药物促进神经再生的机制。从行为水平、细胞水平及分子水平研究Notch信号通路及他汀类药物对脑缺血后神经再生的调控机制,为探讨脑缺血的治疗新策略提供实验依据。
Ischemic cerebralvascular disease endangers human health seriously. The prominent pathological hallmark are focal circulation disorder and the loss of neurons. To regain blood supply and repair the neurons are the two key points of clinical treatment. Although the ultra-early arterial thrombolysis is effective, for most patients, neuron death is unavoidable. How to promote functional recovery is still in research. There is evidence that cerebral ischemia can induce the neural stem cells to proliferate and differentiate in the subventricular zone and the subgranular zone. This process is regulated by the Notch signaling. Simvastatin could promote neurogenesis after cerebral ischemia. But the mechanism is less well understood. This study was undertaken to investigate the role of Notch signaling on neurogenesis after cerebral ischemia, to observe the effect of simvastatin on neurogenesis and the relationship between simvastatin and Notch1 hoping to provide a theoretical and experimental foundation for clinical care on ischemic cerebralvascular diseases.
Objective: To observe the dynamic changes of neurogenesis after focal cerebral ischemia in adult rats, to identify the effect of theγ-secretase inhibitor-DAPT on neurogenesis after focal cerebral ischemia and to observe the influence of simvastatin on neurogenesis and the relationship with Notch1. Methods: Total 120 male Wistar rats were randomly divided into the following groups: Sham group, MCAO group, DAPT group and simvastatin group, 6 rats in each group. Rats in experimental groups suffered from focal cerebral ischemia with a nylon suture method. Neurologic impairment was evaluated by Longa five-grade scoring standard. Learning and memory function was tested with Morris water maze. Western-Blot was used to detect Notch1 protein, immunohistochemistry and immunofluorescence for BrdU, BrdU/DCX and BrdU/NeuN expression. The gama-secretase inhibitor-DAPT was used as the blocker of Notch signaling pathway to observe the influence of Notch signaling on neurogenesis after cerebral ischemia. The effect of simvastatin on neurogenesis and its relationship with Notch1 was investigated. Results: (1) From day 3 after ischemia, BrdU and BrdU/DCX double-labeled positive cells began to increase, peaked at day 14, started to decrease at day 21, and more evident at day 28. BrdU/NeuN double-labeled positive cells appeared at day 3 after ischemia, began to increase at day 7, peaked at day 21, then decreased from day 28. (2) After blocking Notch signaling pathway, the escape latency shortened compared with the MCAO group (P<0.05). Notch1 protein expression at different time points was reduced. At each time point the BrdU-positive cells were more than the sham group, but less than the MCAO group (P<0.05). The trend of BrdU/DCX consistented with BrdU. But the BrdU/NeuN double-labeled positive cells were more than the MCAO group at the same time point. (3) The escape latency of simvastatin group was obviously shorter than the MCAO group (P<0.05). Western-Blot result showed significantly decreased expression of Notch1. BrdU, BrdU/DCX and BrdU/NeuN positive cells were more than the same time point of MCAO (P<0.05). Conclusions: (1) Proliferation and differentiation of endogenous neural stem cells can be induced by cerebral ischemia. (2) Notch signaling passway play a key role in ischemia-induced neurogenesis. (3) Simvastatin could promote neurogenesis and functional recovery after cerebral ischemia. The mechanism may be achieved by influencing the activity of Notch signaling.
引文
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