目的研究中药复方金思维对APPV717Ⅰ转基因小鼠海马神经损伤的保护作用。方法将3月龄的APPV717Ⅰ转基因小鼠随机分为模型组,多奈哌齐治疗组(0.92 mg/kg),金思维小、中、大剂量(0.075、0.15、0.3g/kg)治疗组,并以同月龄遗传背景相同的C57BL/6J小鼠作为正常对照组,每组6只,每天ig给药1次。给药8个月后(11月龄)用Morris水迷宫进行行为学测试,用电镜观察海马CA1区超微结构变化,同时用免疫组化方法观察海马CA1区Shank1蛋白的表达变化。结果行为学检测显示,金思维治疗组与模型组相比逃避潜伏期显著缩短(P<
0.05),目标象限游泳时间明显延长(P<
0.05、0.01),并且与对照组比较无显著差异。海马超微结构显示,模型组小鼠海马CA1神经元出现明显变性及坏死,突触结构不完整,数量明显减少。而金思维各剂量组与模型组相比,剂量依赖性的减轻神经元变性、坏死,增加突触的数目。突触相关蛋白Shank1,模型组小鼠海马CA1区Shank1阳性细胞总数、总面积以及阳性细胞积分吸光度与对照组相比明显减少(P<
0.05、0.01),而金思维治疗组与模型组相比能显著提高Shank1阳性细胞总数、总面积以及阳性细胞积分吸光度(P<
0.05、0.01)。结论金思维能明显改善APPV717Ⅰ转基因小鼠海马神经损伤,增加突触相关蛋白Shank1的表达,进而改善了APPV717Ⅰ转基因小鼠的学习记忆能力。

Objective To investigate the protection of Compound JSW prescription on nerve injury of in the hippocampal area the APPV717Ⅰ transgenic mice.Methods Three-month-old APPV717Ⅰ transgenic mice(30) were randomly divided into three groups by ig administration of Compound JSW prescription at doses of 0.075,0.15,or 0.3 g/kg/d,a group by ig administration of Donepezil at dose of 0.92 mg/kg/d,an APPV717Ⅰ transgenic model group,and a normal group by ig administration of distilled water.APPV717Ⅰ transgenic mice were administered with Compound JSW prescription for eight monthes.The spatial memory ability was measured in Morris water maze.The nerve injury in the hippocampal CA1 region was observed by electronic microscopy.The number of Shank1 positive cells,total area coverd by Shank1,and integral optical density in CA1 subfield within the hippocampus were determined using immunohistochemical stains and Image-Pro plus analysis.Results After eight-month treatment with Compound JSW prescription,the mean escape latency period was significantly shortened(P0.05),and the target quadrant swimming time was significantly lengthened (P0.05 and 0.01) compared to the APPV717Ⅰ transgenic model mice.The ultrastructure of hippocampal CA1 region showed Compound JSW prescription ameliorated the denaturation and necrosis of neurons and increased the amount of nerve synapse with integral structure.Furthermore,the number of Shank1 positive cells,total area coverd by Shank1 and their integral optical density in the hippocampal CA1 area of the APPV717Ⅰ transgenic mice treated with Compound JSW prescription were significantly increased more than those of the APPV717Ⅰ transgenic model mice(P0.05 and 0.01).Conclusion Compound JSW prescription could ameliorate the nerve injury and increase the expression of Shank1 in CA1 subfield within hippocampus,and this might lead to the development of novel treatment for the memory loss of APPV717Ⅰ transgenic mice suffered from Alzheimer's disease.

国家自然科学基金资助项目(30672693,30772288);北京市自然科学基金重点项目(7071005);国家重点基础研究发展计划(“973”计划)项目(2003CB517104);教育部111工程(B08006)