A novel derivative of xanomeline improved memory function in aged mice  

一种新的呫诺美林衍生物改善老年小鼠的记忆能力(英文)

作　　者：崔一卉[1] 司文[1] 殷亮[1] 安述明[1] 金晶[1] 邓世宁[1] 曹晓华[1] 

机构地区：[1]华东师范大学脑功能基因组学教育部重点实验室,上海市科学技术委员会重点实验室,上海200062

出　　处：《Neuroscience Bulletin》2008年第4期251-257,共7页神经科学通报（英文版）

基　　金：the National Basic Research Development Program of China(No. 2003CB716605);National Natural Science Fundation ofChina (No. 30470711, No. 30670682);a grant from Shang-hai Science and Technology Commission (No. 05DJ14007)

摘　　要：Objective To characterize the function of a new xanomeline-derived M 1 agonist, 3-[3-（3-florophenyl-2-propyn- 1- ylthio）-1,2,5-thiadiazol-4-yl]-1,2,5,6- tetrahydro-1-methylpyridine Oxalate （EUK1001）, the acute toxicity and the effects on synaptic plasticity and cognition of EUK1001 were evaluated. Methods To examine the median lethal dose （LD50） of EUK1001, a wide dose range of EUK1001 was administered by p.o. and i.p. in aged mice. Furthermore, novel object recognition task and in vitro electrophysiological technique were utilized to investigate the effects of EUK1001 on recognition memory and hippocampal synaptic plasticity in aged mice. Results EUK1001 exhibited lower toxicity than xanomeline, and improved the performance of aged mice in the novel object recognition test. In addition, bath application of 1 μmol/L EUK1001 directly induced long-term potentiation in the hippocampus slices. Conclusion We conclude that EUK1001 can improve the agerelated cognitive deficits.目的为了分析EUK1001- 新的呫诺美林衍生物的功能性质,本实验以老年小鼠为实验材料,研究了该化合物的急性毒理以及对突触可塑性和识别记忆的影响。方法通过口服及腹腔注射途径,对小鼠进行梯度剂量的毒理学实验,测定EUK1001的半致死剂量(median lethal dose, LD50); 采用新奇物体识别任务和离体脑片电生理学技术研究EUK1001对老年小鼠识别记忆和海马突触可塑性的影响。结果 EUK1001 比呫诺美林呈现出更小的毒副作用。在新奇事物识别实验中,EUK1001 能够显著改善老年小鼠在识别记忆任务中的表现。此外,海马脑片灌流1 μmol/L的EUK1001,能直接诱导产生长时程突触增强(long-term potentiation)。结论 EUK1001能够改善正常老龄化过程中学习记忆能力的衰退。

关 键 词：XANOMELINE EUK 1001 LD50 HIPPOCAMPUS long-term potentiation MEMORY 

分 类 号：R96[医药卫生—药理学]