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学科主题: 药学
题名:
A novel derivative of xanomeline improves fear cognition in aged mice
作者: 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
发表日期: 2010-04-05
DOI: 10.1016/j.neulet.2010.02.031
卷: 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
所属项目编号: NO30670682 ; 05DJ14007
项目资助者: National Natural Science Fund of China ; Shanghai Science and Technology Commission
WOS记录号: WOS:000276673200011
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内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/64996
Appears in Collections:北京大学药学院_期刊论文

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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

Recommended Citation:
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.
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