新型AChE抑制剂胡椒碱衍生物对阿尔茨海默病小鼠的治疗作用评价  

Evaluation of therapeutic effect of novel AChE inhibitor piperine derivative on AD mice

作　　者：孙佳磊 朱仁德 吴静 曹国敏 刘新华[1] 李荣[1] 石静波[1] SUN Jia-lei;ZHU Ren-de;WU Jing;CAO Guo-min;LIU Xin-hua;LI Rong;SHI Jing-bo(School of Pharmacy,Anhui Medical University,Hefei 230032,China)

机构地区：[1]安徽医科大学药学院,安徽合肥230032

出　　处：《中国药理学通报》2023年第11期2064-2069,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 21977001);药学创新基金科研项目(No YXCX202102)。

摘　　要：目的研究胡椒碱衍生物4a对乙酰胆碱酯酶的抑制活性及对阿尔茨海默病(Alzheimer′s disease,AD)小鼠的神经保护的作用。方法雄性C57BL/6J小鼠30只,随机分:(i)空白对照组,(ii)模型组,(iii)多奈哌齐(10 mg·kg^(-1),阳性对照)组,(iv)4a低浓度(20 mg·kg^(-1))组,(v)4a高浓度(40 mg·kg^(-1))组。iii至v组,小鼠给药东莨菪碱(3 mg·kg^(-1))30 min后,口服多奈哌齐和4a,连续10 d,Morris水迷宫实验观察由东莨菪碱诱导的认知功能障碍小鼠的记忆功能。体外实验采用硫黄素-T(ThT)荧光法测定溶液中Aβ的聚集能力,Western blot测定Tau蛋白磷酸化表达,并对化合物4a进行了抑制乙酰胆碱酯酶的动力学研究。结果化合物4a有效抑制AChE活性、Aβ的聚集和Tau蛋白的过度磷酸化,几乎使受损小鼠恢复正常的认知能力。结论化合物4a认为是一种潜在的治疗AD的候选化合物。Aim To study the inhibitory activity of piperine derivative 4a on acetylcholinesterase and its neuroprotective effect on AD mice.Methods Thirty male C57BL/6J mice were randomly divided into:(i)blank control group,(ii)model group,(iii)Donepezil(10 mg·kg^(-1),positive control)group,(iv)4a low concentration(20 mg·kg^(-1))group,and(v)4a high concentration(40 mg·kg^(-1))group.In groups iii to v,30 min after the administration of scopolamine(3 mg·kg^(-1)),Donepezil and 4a were taken orally for 10 consecutive days,and the memory function of scopolamine induced cognitive dysfunction mice was observed in Morris water maze experiment.In vitro,the aggregation ability of Aβin solution was determined by ThT fluorescence method,and the expression of Tau protein phosphorylation was determined by Western blot.The kinetic inhibition of compound 4a on acetylcholinesterase was studied.Results Compound 4a could effectively inhibit the activity of AChE,the aggregation of Aβand the hyperphosphorylation of Tau protein,and almost restored the normal cognitive ability of the damaged mice.Conclusion Compound 4a is considered as a potential candidate compound for the treatment of Alzheimer′s disease.

关 键 词：胡椒碱衍生物 乙酰胆碱酯酶 抑制剂 神经保护 认知功能障碍 阿尔茨海默病 

分 类 号：R-332[医药卫生] R282.71R338.64R345.61R745.7