姜黄素衍生物Cur20通过抑制乙酰胆碱酯酶改善阿尔茨海默病小鼠的记忆和认知能力实验研究

Study on curcumin derivatives Cur20 improving memory and cognitive ability of Alzheimer’s mice by inhibiting acetylcholinesterase

目的 研究姜黄素类似物Cur20对乙酰胆碱酯酶(ACh E)的作用,评价其对阿尔茨海默病(AD)的治疗潜力。方法昆明小鼠随机分4组:对照组、模型组、姜黄素(20μmol·kg^(-1))组和Cur20(20μmol·kg^(-1))组,每天ig给药1次,给药体积10 mL·kg^(-1),除对照组外,其他各组小鼠每次给药30 min后ip东莨菪碱1 mg·kg^(-1)制备AD模型,共给药16 d。第11天开始进行5 d的Morris水迷宫实验,第16天进行Y迷宫实验,检测小鼠的行为认知情况;第17天处死小鼠,取脑分离出海马组织,试剂盒法检测乙酰胆碱(ACh)含量;体外实验检测姜黄素和Cur20对AChE、丁酰胆碱酯酶(BuChE)活性的影响;分子对接实验预测Cur20与AChE的作用模式。结果 小鼠实验结果表明,与模型组比较,Cur20在总游泳距离、游泳速度无显著差异的情况下,能够显著降低水迷宫的逃避潜伏期、增加目标象限的停留时间和路程比例(P<0.05、0.01),明显增加平台穿越次数;在入臂次数无显著性差异的情况下,Cur20组小鼠的自发交替率明显升高;Cur20组海马组织ACh水平显著升高(P<0.01)。体外实验结果表明,Cur20对AChE的半数抑制浓度(IC_(50))为(32.44±4.46)μmol·L^(-1),50μmol·L^(-1) Cur20对BuChE抑制率为(-1.8±2.3)%,Cur20对ACh E的抑制作用具有良好的选择性。分子对接实验表明Cur20能与ACh E的活性部位结合。结论 Cur20能抑制ACh E活性、提高ACh含量,显著改善东莨菪碱所致的学习记忆损伤,可能是一种潜在的治疗AD的药物。

Objective To study the effect of curcumin derivatives Cur20 on AChE and evaluate its therapeutic potential for Alzheimer’s disease(AD).Methods Kunming mice were randomly divided into four groups:Control group,model group,curcumin(20 μmol·kg^(-1)) group and Cur20(20 μmol·kg^(-1)) group,mice were ig administered once a day at a volume of 10 mL·kg^(-1) for a total of 16 days.Except for control group,mice in other groups were given scopolamine 1 mg·kg^(-1) to prepare AD model.Morris water maze test for five days began on day 11,and Y maze test was performed on day 16 to detect the behavioral cognition of mice.On the 17th day,the mice were sacrificed and the hippocampal tissue was isolated from the brain.The ACh content was detected by kit method.The effects of curcumin and Cur20 on the activities of AChE and BuChE were detected in vitro.Molecular docking experiment predicted the interaction mode between AChE and Cur20.Results Compared with model group,Cur20 could significantly reduce the escape latency of water maze,increase the residence time and swimming distance in the target quadrant(P <0.05 and 0.01),and increase the number of platform crossings,when there was no significant difference in total swimming distance and swimming speed.Besides,the percentages of spontaneous alterations in Y maze in Cur20 group was increased than that of model group,while the number of entering the arm was of no significant differences.Moreover,Cur20 showed selective inhibition on acetylcholinesterase,while molecular docking experiment revealed that it could combine with the active site of acetylcholinesterase to exert inhibitory effect.Conclusion Cur20 can inhibit the activity of acetylcholinesterase,increase the content of acetylcholine,and significantly improve the learning and memory damage caused by scopolamine.Cur20 may be a potential drug for the treatment of dementia,especially for Alzheimer’s disease.