Meserine对胆碱酯酶活性及东莨菪碱诱导痴呆小鼠学习记忆的影响

中国临床药理学与治疗学 ›› 2013, Vol. 18 ›› Issue (9): 969-975.

Meserine对胆碱酯酶活性及东莨菪碱诱导痴呆小鼠学习记忆的影响

江盼¹, 郑兆浠¹, 邵碧云¹, 张奇志², 谢琼², 仇缀百², 王昊¹

¹上海交通大学医学院药理学教研室,上海 200025;
²复旦大学药学院, 上海 201203

收稿日期:2013-03-30 修回日期:2013-06-24 发布日期:2013-09-07
作者简介:江盼,在读硕士研究生,研究方向:阿尔茨海默病治疗药物临床前药效学研究。E-mail: jiangpanwell@126.com; 王昊,副教授,硕士生导师,研究方向:多靶点干预神经退行性疾病药物的研究。E-mail: angela_wanghao@hotmail.com
基金资助:
国家重大新药创制专项(2009ZX09103);国家自然科学基金(2010CB529806);上海科学技术委员会生物医药重点攻关项目(10431902700)

Effects of intranasal administration of meserine on AChE activity and scopolamine-induced amnesia in mice

JIANG Pan¹, ZHENG Zhao-xi¹, SHAO Bi-yun¹, ZHANG Qi-zhi², XIE Qiong², QIU Zhui-bai², WANG Hao¹

¹Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
²School of Pharmacy, Fudan University,Shanghai 201203, China

Received:2013-03-30 Revised:2013-06-24 Published:2013-09-07

摘要/Abstract

摘要： 目的: 考察新型胆碱酯酶抑制剂Meserine对胆碱酯酶活性及东莨菪碱(Scopolamine)诱导的胆碱能障碍痴呆模型小鼠学习记忆的影响。方法: 选取小鼠脑匀浆、血浆、人源重组AChE(rHuAChE)为体外酶源,测定Meserine抑制AChE/BuChE的活性、选择性及酶动力学。通过鼻腔给药后检测脑部AChE活性和ACh浓度评价Meserine对小鼠脑内胆碱能系统的调节。选用避暗及水迷宫实验考察Meserine对痴呆模型小鼠学习记忆功能的影响。结果: Meserine对AChE和BuChE都具有较好的抑制活性,IC₅₀分别为(65.2±3.2) nmol/L和(86.7±4.9) nmol/L,并对rHuAChE呈现非竞争性抑制。经鼻给药Meserine可显著抑制脑内AChE活性、升高ACh水平,且二者变化的时程具有一致性,给药 15 min 后,AChE 抑制活性最强(26.9%),ACh浓度最高(1269.0 ng/g)。行为学实验结果显示,经鼻给药Meserine(10 μg/kg)能显著改善东莨菪碱诱导的痴呆模型小鼠的工作记忆及空间学习能力,较模型组具有统计学差异(P<0.01 vs 东莨菪碱组)。结论: 上述结果提示Meserine为强效非竞争性胆碱酯酶抑制剂,经鼻给药Meserine可通过调节脑内胆碱能系统有效改善东莨菪碱诱导的痴呆模型小鼠的学习记忆功能。

关键词: 阿尔茨海默病, Meserine, 胆碱酯酶抑制剂, 东莨菪碱, 多靶点导向配体

Abstract: AIM: The present study was designed to assess the effects of a novel cholinesterase inhibitor Meserine on cholinesterase activity and cognitive impairment induced by scopolamine in mice.METHODS: Mouse brain homogenate, mouse plasma and recombinant human AChE (rHuAChE) were used to assess the cholinesterase inhibitory activity, selectivity and enzyme kinetics of Meserine in vitro. The AChE activity and ACh level in mice brain were measured to evaluate the in vivo effect of Meserine on brain cholinergic system. Passive avoidance testand Morris water maze test were utilized to verify the efficacy of Meserine on scopolamine-induced amnesia in mice.RESULTS: Meserine possessed good inhibitory activity against AChE and BuChE, with IC₅₀ of (65.2±3.2) nmol/L and (86.7±4.9) nmol/L, respectively. Enzyme kinetics study showed that Meserine was a noncompetitive inhibitor on rHuAChE. After intranasal administration of Meserine, the AChE inhibition and ACh level in brain changed consistently. The peak of AChE inhibition (26.9%) and ACh level (1269.0 ng/g) were reached around 15 min after administration. The results of behavior tests showed that Meserine (10 μg/kg, i.n.) could significantly reverse the cognitive impairments induced by scopolamine in mice (P<0.01 vs Scop) .CONCLUSION: Our results suggested that Meserine was a potent noncompetitive cholinesterase inhibitor. Intranasal administration of Meserine could effectively ameliorate the scopolamine-induced amnesia in mice via modulating brain cholinergic system.

Key words: Alzheimer's disease, Meserine, Cholinesterase inhibitor, Scopolamine, Multi-target- directed ligand

中图分类号:

R965.2

江盼, 郑兆浠, 邵碧云, 张奇志, 谢琼, 仇缀百, 王昊. Meserine对胆碱酯酶活性及东莨菪碱诱导痴呆小鼠学习记忆的影响[J]. 中国临床药理学与治疗学, 2013, 18(9): 969-975.

JIANG Pan, ZHENG Zhao-xi, SHAO Bi-yun, ZHANG Qi-zhi, XIE Qiong, QIU Zhui-bai, WANG Hao. Effects of intranasal administration of meserine on AChE activity and scopolamine-induced amnesia in mice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(9): 969-975.

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