普伐他汀对大鼠坐骨神经压碎损伤功能恢复的影响

Effect of pravastatin on functional recovery from sciatic nerve crush injury in rats

背景:普伐他汀是临床上治疗高胆固醇血症的有效药物,目前发现其在中枢神经损伤的治疗上也能发挥有益作用,然而其机制仍未可知。目的:探究普伐他汀治疗能否加速坐骨神经压碎损伤的功能恢复及其潜在作用机制。方法:将雄性SD大鼠随机分为假手术组(坐骨神经暴露但不损伤+生理盐水灌胃)、阴性对照组(坐骨神经压碎损伤+生理盐水灌胃)、普伐他汀组(坐骨神经压碎损伤+普伐他汀灌胃)。普伐他汀组大鼠术后普伐他汀(5 mg/kg)灌胃治疗1周,其余两组大鼠给予等量生理盐水灌胃。术后观察各组大鼠一般情况;术后第2,4,6,8周末测量各组大鼠的坐骨功能指数;术后8周末测量腓肠肌湿质量比;ELISA法检测血清中炎症细胞因子的水平;组织形态计量学分析坐骨神经有髓神经纤维数目、纤维直径、轴突直径、髓鞘厚度;RT-qPCR检测神经生长因子、脑源性神经营养因子的mRNA表达量,Western blot法检测生长相关蛋白43的蛋白表达量。结果与结论:与阴性对照组相比,普伐他汀组坐骨神经功能指数恢复更快(P<0.05),更接近于假手术组水平,血清中炎症细胞因子肿瘤坏死因子α及白细胞介素6表达更低(P<0.05)且接近假手术组,坐骨神经中神经生长因子、脑源性神经营养因子的mRNA相对表达量增加(P<0.05或P<0.01),坐骨神经中生长相关蛋白43的蛋白相对表达量也明显增加(P<0.05),有髓神经纤维数目增加更多,纤维直径、轴突直径及髓鞘厚度数值更大(P<0.01)且与假手术组更接近。结果说明,普伐他汀的治疗加速了坐骨神经压碎损伤的功能恢复,其可能机制是抑制炎症细胞因子肿瘤坏死因子α及白细胞介素6的表达及促进神经营养因子神经生长因子、脑源性神经营养因子的分泌。

BACKGROUND:Pravastatin is a clinically effective drug for the treatment of hypercholesterolemia and is now found to play a beneficial role in the treatment of CNS injury;however,the mechanism remains unknown.OBJECTIVE:To ascertain the possible mechanism of action and whether pravastatin medication can expedite functional recovery following sciatic nerve crush injury.METHODS:Male Sprague-Dawley rats were randomly assigned into:pravastatin(sciatic nerve crush injury+pravastatin gavage),negative control(sciatic nerve crush injury+saline gavage),and sham operation(sciatic nerve exposure but no injury+saline gavage).While the other two groups received comparable amounts of saline gavage,the pravastatin group received postoperative pravastatin(5 mg/kg)by gavage for 1 week.The general conditions of the rats in each group were observed after operation.Sciatic function index was evaluated at the end of the 2nd,4th,6th,and 8th week after operation,and the wet mass ratio of the gastrocnemius muscle was measured at the end of the 8th week after operation.The levels of inflammatory cytokines in serum were measured using ELISA.Histomorphometrics was used to measure the number of myelinated nerve fibers,fiber diameter,axon diameter,and myelin sheath thickness.RT-qPCR assay was used to measure the relative mRNA expression of nerve growth factor and brain-derived neurotrophic factor,and western blot was used to measure the protein expression of growth-associated protein 43.RESULTS AND CONCLUSION:Compared with the negative control group,the sciatic function index in the pravastatin group recovered faster(P<0.05)and was closer to the level of the sham operation group,the expression of tumor necrosis factorαand interleukin 6 in serum was lower(P<0.05)and close to that of the sham operation group,and the relative mRNA expression of nerve growth factor and brain-derived neurotrophic factor in the sciatic nerve increased(P<0.05 or P<0.01),the relative protein expression of growth-associated protein 43 in the sciatic nerve was also significantly increased(P<0.05),the number of myelinated nerve fibers was increased more,and the values of fiber diameter,axon diameter,and myelin sheath thickness were larger(P<0.01)and closer to those of the sham operation group.To conclude,treatment with pravastatin accelerates functional recovery from sciatic nerve crush injury by a possible mechanism of inhibiting the expression of tumor necrosis factorαand interleukin 6 and promoting the secretion of neurotrophic factors nerve growth factor and brain-derived neurotrophic factor.