目的 研究姜黃素類似物Cur20對乙酰膽堿酯酶（AChE）的作用，評價其對阿爾茨海默病（AD）的治療潛力。方法 昆明小鼠隨機(jī)分4組：對照組、模型組、姜黃素（20 μmol·kg^-1）組和Cur20 （20 μmol·kg^-1）組，每天ig給藥1次，給藥體積10 mL·kg^-1，除對照組外，其他各組小鼠每次給藥30 min后ip東莨菪堿1 mg·kg^-1制備AD模型，共給藥16 d。第11天開始進(jìn)行5 d的Morris水迷宮實(shí)驗(yàn)，第16天進(jìn)行Y迷宮實(shí)驗(yàn)，檢測小鼠的行為認(rèn)知情況；第17天處死小鼠，取腦分離出海馬組織，試劑盒法檢測乙酰膽堿（ACh）含量；體外實(shí)驗(yàn)檢測姜黃素和Cur20對AChE、丁酰膽堿酯酶（BuChE）活性的影響；分子對接實(shí)驗(yàn)預(yù)測Cur20與AChE的作用模式。結(jié)果 小鼠實(shí)驗(yàn)結(jié)果表明，與模型組比較，Cur20在總游泳距離、游泳速度無顯著差異的情況下，能夠顯著降低水迷宮的逃避潛伏期、增加目標(biāo)象限的停留時間和路程比例（P<0.05、0.01），明顯增加平臺穿越次數(shù)；在入臂次數(shù)無顯著性差異的情況下，Cur20組小鼠的自發(fā)交替率明顯升高；Cur20組海馬組織ACh水平顯著升高（P<0.01）。體外實(shí)驗(yàn)結(jié)果表明，Cur20對AChE的半數(shù)抑制濃度（IC₅₀）為（32.44±4.46）μmol·L^-1，50 μmol·L^-1 Cur20對BuChE抑制率為（-1.8±2.3）%，Cur20對AChE的抑制作用具有良好的選擇性。分子對接實(shí)驗(yàn)表明Cur20能與AChE的活性部位結(jié)合。結(jié)論 Cur20能抑制AChE活性、提高ACh含量，顯著改善東莨菪堿所致的學(xué)習(xí)記憶損傷，可能是一種潛在的治療AD的藥物。

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.

R285.5

河南省醫(yī)學(xué)科技攻關(guān)計(jì)劃（聯(lián)合共建項(xiàng)目）（LHGJ20190504）；河南省自然科學(xué)基金資助項(xiàng)目（202300410038）；河南省教育廳科學(xué)技術(shù)研究重點(diǎn)項(xiàng)目資助計(jì)劃（21A350002）