阿司匹林通过促进海马功能性神经再生改善颞叶癫痫慢性期小鼠的空间记忆能力  

Aspirin attenuates cognitive deficits of chronically epileptic mice by promoting the functional integration of newly generated neurons

作　　者：朱坤[1] 胡明[1,2] 杨蓬勃[2] 张建水[2] 陈新林[1,2] 刘建新[1] 

机构地区：[1]西安交通大学医学部基础医学院神经生物学研究所,陕西西安710061 [2]西安交通大学医学部基础医学院人体解剖与组织胚胎学系,陕西西安710061

出　　处：《西安交通大学学报（医学版）》2016年第5期622-626,共5页Journal of Xi’an Jiaotong University（Medical Sciences）

基　　金：国家自然科学基金面上项目资助(No.81171232;81371427)~~

摘　　要：目的评估阿司匹林（aspirin）通过抑制脑内炎症反应对颞叶癫痫（TLE）慢性期小鼠空间学习记忆能力的影响,并从海马神经再生角度初探其机制。方法匹鲁卡品（pilocarpine）制作小鼠TLE模型,在慢性期分别腹腔注射不同剂量阿司匹林（20、60、80mg/kg）或同体积生理盐水,用Western blot和ELISA检测海马环氧化物酶-2（COX-2）和前列腺素E2（PGE2）变化,Morris水迷宫实验评估动物的空间学习记忆能力并观察海马神经元C-fos表达变化,BrdU＋C-fos免疫荧光双标染色观察齿状回新生细胞的功能整合。重复测量（repeated measures）ANOVA比较各组水迷宫潜伏期,One-way ANOVA方法分析各组染色阳性细胞计数结果。结果腹腔注射60、80mg/kg阿司匹林可以明显降低海马COX-2和PGE2的表达（P〈0.01）。与正常同龄对照组比较,TLE慢性期动物在Morris水迷宫任务中的表现明显下降,而与生理盐水注射模型组比较,阿司匹林治疗组明显缩短了定位航行实验第3～5天的潜伏期并提高了空间探索实验中穿越目的象限的时间比例（P〈0.01）。BrdU＋C-fos免疫荧光染色结果显示阿司匹林组动物齿状回双标细胞数量较生理盐水注射组明显增多（P〈0.01）。结论阿司匹林可以改善TLE慢性期小鼠空间记忆能力。通过抑制脑内炎症反应、改善齿状回微环境,促进海马功能性神经再生可能是阿司匹林的治疗作用机制之一。Objective To assess the effects of chronic administration of aspirin on the cognitive deficits and functional integration of newly generated neurons from the dentate gyrus.Methods Pilocarpine was used to induce status epilepticus（SE）in mice（TLE）.At 3 months after SE,the mice were injected i.p.with either aspirin（20,60 and 80 mg/kg）in experimental groups or saline of the same volume in the control group for 10 weeks.The protein levels of COX-2 and PGE2 in the hippocampus were detected by Western blot or enzyme linked immunosorbent assay,respectively.Morris water maze（MWM）task was employed to assess the spatial cognitive ability of the mice.The newly generated neurons that were integrated into memory circuits were visualized by detecting activation of BrdU～＋cells,following a recall of spatial memory test at the chronic stage of TLE.Repeated measures ANOVA or One-way ANOVA methods were used to analyze the escape latencies in MWM task or other data respectively.Results Ten-week treatment with 60 mg/kg or 80 mg/kg of aspirin decreased significantly the levels of COX-2 and PGE2 in the hippocampus when compared with saline treatment（P〈0.01）.On the last three days of the place navigation test,saline-treated epileptic mice took a much longer latency than normal mice or aspirin-treated mice with the dose of 60 mg.In the spatial probe test,the mice in the saline group spent significantly less time in the target quadrant than the mice in apirin groups（P〈0.01）.When compared with the saline-treated mice,more double labeling cells of BrdU＋C-fos in the subgranular zone-granule cell layer（SGZ-GCL）were found in the mice with 10-week aspirin treatment（P〈0.01）.Conclusion Chronic treatment of aspirin attenuates cognitive deficits of epileptic mice.Inhibiting brain inflammation and consequently restoring functional integration in the hippocampus may partially contribute to the therapeutic effect of aspirin.

关 键 词：阿司匹林 颞叶癫痫 海马 神经再生 学习记忆 环氧化物酶-2(COX-2) 前列腺素E2(PGE2) 

分 类 号：R322.8[医药卫生—人体解剖和组织胚胎学]