| 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.
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