烟碱类似物ZY-1对淀粉样蛋白产生及转基因阿尔茨海默病小鼠学习记忆的作用

摘要/Abstract

摘要：目的：观察烟碱类似物ZY-1在细胞水平上对Aβ产生的影响及对转基因阿尔茨海默病小鼠学习记忆的作用。方法：在转染高表达烟碱受体亚型的SH-EP1-α4β2 nAChR细胞株进行放射配基结合实验；Western blotting检测ZY-1对于转染了APP695质粒的SH-EP1-α4β2 nAChR细胞产生Aβ的影响；在双转基因阿尔茨海默病小鼠B6C3-Tg（APPswe/PSEN1dE9）85Dbo/J品系通过Morris水迷宫试验和跳台试验观察ZY-1对小鼠学习记忆的影响。结果：1.受体亚型结合分析，亲和力常数Ki＝21.5 mol·L^-1，亲和力很高，显示ZY-1有α4β2亚型结合特异性。2. 烟碱激动剂尼古丁和ZY-1可以显著降低细胞内Aβ水平。3. Morris水迷宫试验和跳台试验表明，ZY-1中、高剂量对模型小鼠的空间学习记忆有显著改善作用。结论：ZY-1可能具备了作为AD治疗药物进一步开发的潜力，确切的成药性仍需进一步的试验来证明。

关键词:阿尔茨海默病,转基因小鼠,受体结合分析,烟碱受体

Abstract:Objective:To observe the effects of ZY-1, a nicotine analogue, on in vitro receptor binding and β-amyloid (Aβ) production and in vivo transgenic Alzheimer’s disease mice.Methods:Receptor binding assay was carried out in SH-EP1-α4β2 nAChR cell line highly expressing α4β2 nAChR; Western blotting was used to detect the effects of ZY-1 on amyloid protein production in the SH-EP1-α4β2 nAChR cell line transfected with APP695 plasmid; and effects of ZY-1 on learning and memory were measured in B6C3-Tg（APPswe, PSEN1dE9）85Dbo/J mice.Results:1. Receptor binding assay showed that Ki is 21.5 n mol•L-1, suggesting specific binding of ZY-1 to α4β2 nAChR; 2. ZY-1(1 μmol•L-1) reduced intracellular production of Aβ; 3. Middle (0.50 mg•kg-1) and high dose (0.75 mg•kg-1) of ZY-1 improved learning and memory of transgenic mice in Morris water maze and platform test.Conclusion:ZY-1 might be of potential to be an AD therapeutic agent, but the druggability remains to be further confirmed.

Key words:Alzheimer's disease,transgenic mice,receptor binding assay,nicotinic acetylcholine receptor

聂惠贞, 王泽剑, 赵文娟, 卢金淼, 张璨, 骆庆和, 王玉亮, 高翔, 殷明. 烟碱类似物ZY-1对淀粉样蛋白产生及转基因阿尔茨海默病小鼠学习记忆的作用[J]. 神经药理学报, 2011, 1(1): 26-31.

NIE Hui-Zhen, WANG Ze-Jian, ZHAO Wen-Juan, LU Jin-Miao, ZHANG Can, LUO Qing-He, WANG Yu-Liang, GAO Xiang, YIN Ming. Effects of nicotine analog ZY-1 on β-amyloid production and learning and memory in transgenic Alzheimer disease mice[J]. Acta Neuropharmacologica, 2011, 1(1): 26-31.

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