Attenuation of neurodegenerative phenotypes in Alzheimer-like presenilin 1/presenilin 2 conditional double knockout mice by EUK1001, a promising derivative of xanomeline.
Attenuation of neurodegenerative phenotypes in Alzheimer-like presenilin 1/presenilin 2 conditional double knockout mice by EUK1001, a promising derivative of xanomeline.
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DOI：
10.1016/j.bbrc.2011.05.120
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发表时间：
2011-07
影响因子：
3.1
通讯作者：
Dong Wang;Liguo Yang;Jingjing Su;Yan Niu;Xiaoping Lei;J. Xiong;Xiaohua Cao;Yinghe Hu;B. Mei-B
中科院分区：
文献类型：
--
作者：
Dong Wang;Liguo Yang;Jingjing Su;Yan Niu;Xiaoping Lei;J. Xiong;Xiaohua Cao;Yinghe Hu;B. Mei-B
M1/M4偏好的毒蕈碱激动剂xanomeline被发现在治疗阿尔茨海默病（AD）的记忆障碍方面有一些益处，但副作用阻碍了进一步的发展。由于对M1毒蕈碱受体的亲和力更高，因此，作为克诺美林的氟化衍生物，EUK 1001可能具有比克诺美林更好的副作用特征。我们现在已经研究了3个月的慢性给药的EUK 1001和克诺美林（0.5毫克/公斤/天）在AD样早老素1/早老素2条件性双敲除（PS cDKO）小鼠的影响。只有EUK 1001被发现显着改善识别记忆的缺陷。组织学分析表明，在EUK 1001处理的PS cDKO小鼠中脑萎缩部分减弱，在克诺美林处理的小鼠中影响最小。这两种化合物都有效地抑制了PS cDKO小鼠脑tau磷酸化的升高，但都没有抑制增加的炎症反应。这些结果表明，在PS cDKO小鼠中，EUK 1001在减弱几种AD样神经退行性表型方面显示出优于咕诺美林。这些结果表明，需要进一步研究EUK 1001治疗AD的开发。
The M1/M4-preferring muscarinic agonist xanomeline was found to have some benefit in the treatment of the memory impairment of Alzheimer’s disease (AD), but side effects precluded further development. EUK1001, a fluorinated derivative of xanomeline, because of greater affinity for M1 muscarinic receptors, is likely to have a significantly better side effect profile than xanomeline. We have now studied the effects of 3-month chronic administration of EUK1001 and xanomeline (0.5 mg/kg/day) in AD-like presenilin 1/presenilin 2 conditional double knockout (PS cDKO) mice. Only EUK1001 was found to significantly ameliorate the deficit in recognition memory. Histological analysis demonstrated partial attenuation of the brain atrophy in EUK1001-treated PS cDKO mice and minimal effect in the xanomeline-treated mice. Both compounds effectively suppressed the elevation of brain tau phosphorylation in the PS cDKO mice, but neither inhibited the increased inflammatory responses. These results indicate that EUK1001 showed superiority to xanomeline with regard to attenuation of several AD-like neurodegenerative phenotypes in PS cDKO mice. These results suggest further investigation of the development of EUK1001 for the treatment of AD is indicated.