瑞舒伐他汀钙联合多奈哌齐对阿尔茨海默病模型小鼠炎症反应的影响

Effects of rosuvastatin calcium combined with donepezil on inflammatory response in mice with Alzheimer’s disease

摘要:

目的：研究瑞舒伐他汀钙联合多奈哌齐对阿尔茨海默病模型小鼠炎性因子表达的影响。方法：APP/PS1双转基因小鼠随机分为模型组、多奈哌齐组、瑞舒伐他汀钙组和联合治疗组，每组10只。多奈哌齐组剂量为1.3 mg/（kg·d），瑞舒伐他汀钙组剂量为1 mg/（kg·d），联合治疗组采用瑞舒伐他汀钙和盐酸多奈哌齐联合给药，剂量分别为1 mg/（kg·d）和1.3 mg/（kg·d），3组均采用灌胃给药。模型组不予治疗。Morris水迷宫实验测试各组小鼠逃避潜伏期，亚甲蓝染色观察各组小鼠海马神经元损伤的形态改变，免疫组化法检测小鼠海马白细胞介素-1β（interleukin-1β，IL-1β）、肿瘤坏死因子- α（tumor necrosis factor-α，TNF-α）和p38丝裂原活化蛋白激酶（p38 mitogen-activated protein kinases，p38MAPK）表达，Western blot检测小鼠海马IL-1β、TNF-α和p38MAPK含量。结果：治疗后多奈哌齐组、瑞舒伐他汀钙组和联合治疗组逃避潜伏期缩短，但联合治疗组好于多奈哌齐组、瑞舒伐他汀钙组。免疫组化显示，与模型组比较，联合治疗组IL-1β（0.37±0.05 vs. 0.52±0.09，P=0.001）、TNF-α（0.42±0.08 vs. 0.69±0.11，P=0.002）和p38MAPK（0.39±0.06 vs. 0.61±0.10，P=0.001）平均光密度的表达明显降低。Western blot检测结果再次验证，与模型组比较，多奈哌齐组、瑞舒伐他汀钙组和联合治疗组IL-1β、TNF-α和p38MAPK蛋白表达水平降低。结论：瑞舒伐他汀钙联合多奈哌齐对APP/PS1转基因小鼠的空间学习记忆和神经元损伤有明显的改善作用，可能通过抑制p38MAPK通路，共同降低海马中的炎性因子产生。

Abstract:

Objective：To study the effects of rosuvastatin calcium combined with donepezil on the expression of inflammatory factors in rats with Alzheimer’s disease. Methods：APP/PS1 double transgenic mice were randomly divided into model group，donepezil group，rosuvastatin group and combined treatment group，10 mice in each group. The dose of donepezil hydrochloride group[donepezil 1.3 mg/（kg·d） infusion]，rosuvastatin calcium group [rosuvastatin calcium 1 mg/（kg·d） infusion]，combined treatment group[rosuvas－tatin calcium 1 mg/（kg·d），donepezil 1.3 mg/（kg·d） infusion]. The model group was not treated. Morris water maze was used to test the escape latency of mice in each group. Methylene blue staining was used to observe the morphological changes of hippocampal neurons in each group. Immunohistochemical method was used to detect the expression of IL-1β，TNF-α and p38MAPK in hip－pocampus of mice. Western blot was used to detect the content of IL-1β，TNF-α and p38MAPK in hippocampus of mice. Results：After treatment，the escape latency was shortened in donepezil group，rosuvastatin group and combined therapy group，but the combined therapy group was better than donepezil group and rosuvastatin group. The results of immunohistochemistry showed that the average optical density of IL-1β（0.37±0.05 vs. 0.52±0.09，P=0.001），TNF-α（0.42±0.08 vs. 0.69±0.11，P=0.002） and p38MAPK（0.39±0.06 vs. 0.61±0.10，P=0.001） in combined treatment group were lower than that in model group. The results of Western blot showed that the expression of IL-1β，TNF-α and p38MAPK in donepezil group，rosuvastatin group and combined treatment group were lower than that in model group. Conclusion：Rosuvastatin calcium combined with donepezil can significantly im－prove the spatial learning，memory and neuron damage of APP/PS1 transgenic mice. It may decrease the production of inflammatory factors in hippocampus by inhibiting p38MAPK pathway.