普伐他汀对脑缺血大鼠的神经保护及神经发生的作用

目的研究中枢神经系统缺血损伤后,普伐他汀的神经保护和促进神经发生作用。方法采用线栓法造成大鼠大脑中动脉的暂时性缺血,在以下时间点给予普伐他汀：伤后6h,伤后每天直至伤后14天。用神经学评分、平衡实验和旋转实验评价伤后神经学恢复情况。检测血清胆固醇和甘油三酯的含量,计算脑梗塞面积。通过三染色法（BrdU, DCX, NeuN染色）研究普伐他汀对神经发生的作用。结果各组间血清胆固醇和甘油三酯无显著性差异;与对照组相比,实验组动物术后旋转实验评分显著性增加,梗塞面积减小;普伐他汀显著增加了齿状回和脑室下区的BrdU阳性细胞数,并增加了齿状回、脑室下区和纹状体中的BrdU/DCX阳性细胞数。结论中枢神经系统损伤早期重复使用低剂量的普伐他汀是相对安全的,并能够显著改善伤后的神经功能恢复,减少梗死面积。普伐他汀能够诱导大鼠齿状回及脑室下区的神经发生并增加纹状体中迁移神经元的数量,这与普伐他汀的降脂作用无关。

Effects of Pravastatin on neuroprotection and neurogenesis after cerebral ischemia in rats

OBJECTIVE: Statins inhibit hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity and lower total serum cholesterol levels. We investigated the effects of Pravastatin on neuroprotection and neurogenesis in the dentate gyrus (DG), subventricular zone (SVZ) and striatum after cerebral ischemia in rats. METHODS: The filament method was used for temporary middle cerebral artery occlusion (tMCAO). Pravastatin or saline post-ischemically were administered at subsequent time points: 6 h after tMCAO, and then on every subsequent day up to day 14 after tMCAO. Neurological outcome was investigated by using a neuroscore, the beam balance test and the rotarod test. Cholesterol and triglycerides levels were determined by blood sample analysis prior to sacrifice. Infarct area was calculated by microtubule-associated protein 2 (MAP2) staining. Neurogenesis was evaluated by triple staining with bromodeoxyuridine (BrdU), doublecortin (DCX), and neuronal nuclei (NeuN). RESULTS: Compared with the control groups, Pravastatin treated animals were significantly improved in neurological outcome in rotarod test, with smaller infarct size. Pravastatin increased BrdU-positive cells number in the DG (P = 0.0029) and the SVZ (P = 0.0280) but not in the striatum (P = 0.3929). Furthermore, Pravastatin increased BrdU-labeled DCX positive cells number in the DG (P = 0.0031), SVZ (P = 0.0316) and striatum (P = 0.0073). We also observed a DCX-positive cells stream from the SVZ to the striatum, suggesting a migration route of those immature neurons. No significant differences of total serum cholesterol and triglycerides were observed between groups. CONCLUSION: The Pravastatin administration strategy is safe and could promote neurological recovery in ischemic stroke. Pravastatin induces neurogenesis in the DG and SVZ, and increases the number of migration cells in the striatum. These effects are independent of the cholesterol-lowering property of Pravastatin.