Effect Of Simvastatin On Hippocampal Neurogenesis In Rat Focal Cerebral Ischemia

Background and Purpose Cerebrovascular disease which causes serious harm to human health is among the common causes of death in the first three, second only to cardiovascular disease and cancer. The high morbidity of cerebrovascular disease is a heavy psychological and financial burden to the family and society. Cerebrovascular disease is generally divided into ischemic cerebrovascular disease (ischemic cerebrovascular disease, ICVD) and hemorrhagic cerebrovascular disease. Ischemic cerebrovascular disease accounts for most of cerebrovascular diseases, and the main pathophysiological mechanism is the disfunction of brain blood circulation resulting in injury or necrosis of nerve cells caused by ischemia or hypoxia. There is no ideal treatment for ischemic cerebrovascular disease. The results show that the regeneration of nerve cells derived from neural stem cells in the central nervous system occurs after cerebral ischemia. The hippocampus dentate gyrus (DG) and the subventricular zone are the main parts of nerve regeneration. Simvastatin is a widely used statins. Recent studies show that simvastatin can not only lower blood lipids, but also protect nerve function, and promote nerve regeneration. The hippocampus dentate gyrus (DG) where neural stem cells continue to proliferate and differentiate is an important place of neurogenesis of the brain. Hippocampus is closely related to learning and memory functions and is often involved in cerebral ischemia.Reports confirm that prophylactic use of simvastatin can significantly reduce the incidence of ischemic cerebrovascular disease and ischemic injury. However, whether the use of simvastatin in the acute phase of ischemic cerebrovascular disease could promote neuronal regeneration and nerve function is rarely studied. This study discussed the issue to provide the basis for the treatment of ischemic cerebrovascular disease.Methods In this study, we used the middle cerebral artery occlusion (MCAO) model. 90 male Wistar rats were randomly divided into three groups. A: sham group, n=30. B group: MCAO group, n=30. C: simvastatin group (MCAO+simvastatin), n=30. Each group was divided into five sub-groups according to five time points (3d, 7d, 14d, 21d, 28d) after ischemia, each with 6 animals. All animals were given the 5- bromo-deoxyuridine (BrdU) of 1g/L of the working concentration by intraperitoneal injection of 2 times per day with an interval of 8 hours, starting at 24h after ischemia and continuing 3 days according to 50mg/kg, Only C group animals were given simvastatin of 2g/L concentration by intraperitoneal injection of once per day ,starting from 24h after ischemia and continuing 7 days according to 1mg/kg . We used Morris water maze to test learning and memory.ability of the rats. We measured Brdu positive cells in the hippocampus by immunohistochemistry.Results the rats which had been trained by Morris water maze showed decline in memory function after 28 days and their escape latency prolonged. MCAO group had significant difference statistically compared with the sham group (P <0.01).At the same time point the escape latency of simvastatin group decreased compared with MCAO group, and the difference was significant (P <0.05). 3 days after cerebral ischemia, hippocampus of sham group, MCAO group and the simvastatin group showed different degrees of BrdU-positive cells by light microscope, showing a brown colored granules, mainly in the nucleus. BrdU-positive cells of sham group were scattered, and small lightly stained nuclei were round. BrdU-positive cells in the hippocampus of the other two groups increased significantly. After ischemia, BrdU-positive cells began to increase in 3 days and reached the peak in 14 days.Then BrdU-positive cells remained at high level and began to decline in 21 days and decreased significantly in 28 days. The positive cells of simvastatin group were significantly increased compared with the MCAO group, and the difference was statistically significant (P<0.05).Conclusion 1. Hippocampal neurogenesis at least begins 3 days after ischemia , reaches the peak in the 14 days and begins to decrease in 21 days.. 2. Simvastatin is effective for promoting Hippocampal neurogenesis and improving learning and memory function after cerebral ischemia...