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A novel derivative of xanomeline improves fear cognition in aged mice
Si, Wen1; Zhang, Xuliang1; Niu, Yan2; Yu, Huiting3; Lei, Xiaoping2; Chen, Huanxin4; Cao, Xiaohua1
关键词Xanomeline EUK1001 Hippocampus Long-term potentiation Memory
刊名NEUROSCIENCE LETTERS
2010-04-05
DOI10.1016/j.neulet.2010.02.031
473期:2页:115-119
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Neurosciences
研究领域[WOS]Neurosciences & Neurology
关键词[WOS]MUSCARINIC ACETYLCHOLINE-RECEPTOR ; RAT HIPPOCAMPAL SLICES ; LONG-TERM POTENTIATION ; ALZHEIMERS-DISEASE ; MEMORY FUNCTION ; AGONIST ; INDUCTION ; ENHANCEMENT ; ANTAGONIST ; PLASTICITY
英文摘要

The M1/M4 muscarinic acetylcholine receptor agonist xanomeline can significantly improve the cognitive function, but the intolerable side effects limit its clinical usefulness. Our recent study has reported a novel derivative of xanomeline, 3-[3-(3-(3-florophenyl)-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine oxalate (EUK1001), exhibited higher affinity of mAChRs and less side effects relative to xanomeline. In the present study, we further utilized behavioral and electrophysiological techniques to investigate the effects of EUK1001 on fear cognition and hippocampal long-term potentiation (LTP) in aged mice. Behavioral testing showed that 0.1, 0.5 or 1.0 mg/kg EUK1001 group, like 1.0 mg/kg xanomeline group, exhibited better performance in contextual fear conditioning and passive avoidance test than vehicle-controls. In the cued fear conditioning test, just 0.5 or 1.0, but not 0.1 mg/kg EUK1001, significantly enhanced the levels of freezing response. In addition, theta-burst stimulation (TBS) induced the significant larger hippocampal LTP in brain slices perfused with artificial cerebrospinal fluid (ACSF) containing 0.01 mu M EUK1001 or in brain slices from aged mice injected intraperitoneally (i.p.) with EUK1001. This enhancing effect was blocked by 0.25 mu M pirenzepine, a selective M1 antagonist. Together, these results show that EUK1001 can enhance fear cognition and synaptic plasticity via the activation of M1 muscarinic acetylcholine receptors. Thus, EUK1001 may possibly represent a promising lead compound for the treatment of Alzheimer′s disease and age-related cognitive deficits. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

语种英语
WOS记录号WOS:000276673200011
项目编号NO30670682 ; 05DJ14007
资助机构National Natural Science Fund of China ; Shanghai Science and Technology Commission
引用统计
被引频次:9[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/64996
专题北京大学药学院
北京大学药学院_药物化学系
作者单位1.E China Normal Univ, Shanghai Key Lab Brain Funct Genom, Key Lab Brain Funct Genom, Minist Educ, Shanghai 200062, Peoples R China
2.Peking Univ, Sch Pharmaceut Sci, Beijing 100083, Peoples R China
3.Shanghai Municipal Ctr Dis Control & Prevent, Dept Vital Stat, Shanghai 200336, Peoples R China
4.Univ Florida, Dept Neurosurg, Gainesville, FL USA
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GB/T 7714
Si, Wen,Zhang, Xuliang,Niu, Yan,et al. A novel derivative of xanomeline improves fear cognition in aged mice[J]. NEUROSCIENCE LETTERS,2010,473(2):115-119.
APA Si, Wen.,Zhang, Xuliang.,Niu, Yan.,Yu, Huiting.,Lei, Xiaoping.,...&Cao, Xiaohua.(2010).A novel derivative of xanomeline improves fear cognition in aged mice.NEUROSCIENCE LETTERS,473(2),115-119.
MLA Si, Wen,et al."A novel derivative of xanomeline improves fear cognition in aged mice".NEUROSCIENCE LETTERS 473.2(2010):115-119.
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