新型双配基AChEI美普色胺改善东莨菪碱致小鼠学习记忆功能障碍的研究

(-)-Mep-S as a novel dual-binding AChEI to ameliorate scopolamine-induced learning and memory impairment in mice

目的探究左旋美普他酚与5-羟色胺的杂合物美普色胺[(-)-Mep-S]对东莨菪碱诱发小鼠学习记忆功能障碍的改善作用。方法应用分子对接技术分析(-)-Mep-S与hAChE之间的结合;利用体内外实验观察(-)-Mep-S对AChE活性的影响;通过Morris水迷宫行为学实验分析小鼠学习记忆能力;应用旷场试验检测(-)-Mep-S对小鼠运动能力影响。结果分子对接分析显示,(-)-Mep-S与hAChE的催化位点和外周阴离子位点存在较强结合。(-)-Mep-S明显抑制小鼠前脑来源和人SH-SY5Y细胞来源的AChE活性,其IC50值均低于阳性对照药利斯的明。在水迷宫实验中,(-)-Mep-S(2.5 mg/kg)治疗的小鼠在第4天的上台潜伏期显著缩短(P<0.05),且在第5天的空间探索试验中,小鼠在靶象限的游泳距离百分比和时间百分比显著升高(P<0.05);而0.5 mg/kg剂量下(-)-Mep-S未能表现出明显作用;(-)-Mep-S能显著抑制东莨菪碱所致的小鼠前脑AChE活性增强(P<0.05)。另外,旷场试验提示(-)-Mep-S改善东莨菪碱所致小鼠学习记忆功能障碍的作用并不是由于运动能力的差异所造成的。结论(-)-Mep-S能有效抑制AChE活性,从而改善东莨菪碱诱发小鼠学习记忆功能障碍。

Objective To explore the effect of(-)-meptazinol-serotonin hybrid,[(-)-Mep-S]on scopolamine-induced learning and memory impairment in mice.Methods The binding of(-)-Mep-S and hAChE was analyzed by molecular docking.The effect of(-)-Mep-S on AChE activity was observed in vivo and in vitro.The effect of(-)-Mep-S on learning and memory impairment induced by scopolamine was examined in Morris water maze test in mice.The effect of(-)-Mep-S on the motor behaviors of mice was detected by open field test.Results Molecular docking analysis revealed that(-)-Mep-S binded to human AChE.In parallel,(-)-Mep-S overtly inhibited the activity of AChE derived from mouse forebrain and SH-SY5Y neuronal cells,and IC50 values were lower than those of the positive control drug rivastigmine.In the Morris water maze test,mice treated with(-)-Mep-S(2.5 mg/kg)showed significantly reduced latency on day 4(P<0.05).Moreover,they exhibited significantly greater percentage of distance travelled and percentage of time spent in the target quadrant in the probe trial on day 5(P<0.05).(-)-Mep-S at 0.5 mg/kg did not show any significant effects.In addition,(-)-Mep-S inhibited the enhancement of forebrain AChE activity induced by scopolamine(P<0.05).The open field test showed that the effect of(-)-Mep-S on scopolamine-induced learning and memory impairment was not due to the difference on the motor behaviors of mice.Conclusion(-)-Mep-S can effectively inhibit AChE activity and ameliorate scopolamine-induced learning and memory impairment in mice.