Abstract: Objective To evaluate the effects of Aricept on the presenilin-1 (PS-1) expression in rathippocampus during chronic cerebrovascular insufficiency (CVI).Methods Total 90 male Wistar rats were randomly assigned to pseudo-operation control group,CVI group, and CVI plus Aricept group. The CVI model was set up by the permanent of bilateralocclusion of both common carotid arteries (2-VO). The subgroups were determined by thesacrifice time on the first day, first week, and first month after 2-VO. PS-1 positive neuronalcells were observed by immunoelectron microscopy. The amyloid β42 (Aβ42) and PS-1 level ofhippocampus tissues were analyzed by Western Blotting.Results Compared with control group, CVI group had less survived rats than Aricept group (Firstday 7 vs 8, first week 5 vs 7). Compared to CVI group, Aricept group had much less chronicischemic impairment exhibitions, more PS-1 positive gold particles, and better endoplasmicreticulum structure. The time course study by Western blotting showed that in CVI group PS-1substantially increased at the first day after operation, and achieved the peak almost 2.3 foldersthan pseudo-operation group at the first week, then went down to lower level of pseudo-operationgroup at the first month. Aricept group showed sub-acute upregulation that PS-1 increasedmoderately at the first day, and kept slightly going up, then increased to the peak around twofolders than pseudo-operation group at the first month. Aβ42 of CVI group increased with theischemic duration and was 3.5 folders than pseudo-operation group. Contrastly, Aβ42 of Ariceptgroup increased more slowly and was significantly less than CVI group’s (P <0.01).Conclusion It is concluded that Aricept has neuroprotective effect against CVI in PS-1 positiveneuronal cells and can decrease Aβ42 production after cerebral ischemia.

Key words: Aricept; Presenilin-1; Cerebrovascular insufficiency; Rats

摘要：

目的 观察多奈哌齐对慢性脑灌注不足（CVI）大鼠脑早老素-1（PS-1）蛋白水平的影响。方法 90只雄性Wistar大鼠随机分为假手术对照组、单纯脑缺血组和多奈哌齐（安理申，卫材公司）组，按照取材时间又分为术后1天、1周及1月组，每组各10只。采用永久性结扎双侧颈总动脉建立CVI模型。常规及免疫电镜观察术后1周时海马区缺血性改变以及PS-1的表达。蛋白免疫印迹检测PS-1及其酶解产物Aβ42不同时间点的改变。结果 与对照组相比，单纯脑缺血组术后1周存活7只，1月5只；多奈哌齐组术后1周8只，1月7只。常规电镜显示单纯缺血组呈慢性缺血性改变，多奈哌齐组缺血性改变明显减轻。免疫电镜显示，单纯缺血组内质网破碎明显，PS-1胶体金颗粒散在分布。多奈哌齐组内质网结构尚完整，分布均匀。蛋白免疫印迹结果显示，与假手术对照组相比，单纯脑缺血组PS-1在第1天即明显升高，1周后达高峰，升高为2.3倍，1月后又低于对照组水平。多奈哌齐组在术后第1天轻度升高，1周后继续上调，1月后达高峰，约为对照组2倍，呈亚急性改变。Aβ42在单纯缺血组随着缺血时间延长而持续升高，术后第1月时升高约3.5倍，而多奈哌齐组各时间点Aβ42含量升高则明显减慢。与单纯缺血组比较，术后1月时多奈哌齐组显著减少Aβ42的生成（P <0.01）。结论 多奈哌齐对PS-1阳性神经细胞有保护作用，同时可以减少脑缺血后Aβ产生。

关键词: 多奈哌齐; 早老素-1; 脑灌注不足; 大鼠