Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice
Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice
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Tacrine(10)-hupyridone 是一种双结合乙酰胆碱酯酶抑制剂，可有效减轻东莨菪碱引起的小鼠认知损伤
DOI：
10.1007/s11011-018-0221-7
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发表时间：
2018-08-01
影响因子：
3.6
通讯作者：
Han, Yifan
中科院分区：
文献类型：
--
作者：
Chen, Huixin;Xiang, Siying;Han, Yifan
他克林（10）-石杉碱甲吡啶酮（A10 E）是由他克林和石杉碱甲的一个片段经修饰而成的双结合乙酰胆碱酯酶（AChE）抑制剂。我们发现A10 E以混合竞争方式有效抑制AChE，IC 50为26.4 nM，比他克林和石杉碱甲更有效。最重要的是，我们首次证明了A10 E在不影响小鼠运动功能的情况下减弱了东莨菪碱诱导的认知障碍。A10 E有效地减弱了学习和记忆障碍，其程度与用于治疗阿尔茨海默病（AD）的AChE抑制剂多奈哌齐相似。此外，A10 E还能显著降低小鼠脑内AChE活性，提示A10 E可能通过脑血屏障。综上所述，我们的结果表明，A10 E，一个设计的双结合AChE抑制剂，可以有效地逆转认知障碍，表明A10 E可能提供治疗AD的疗效。
Tacrine(10)-hupyridone (A10E) was designed as a dual-binding acetylcholinesterase (AChE) inhibitor from the modification of tacrine and a fragment of huperzine A. We have found that A10E effectively inhibited AChE in a mixed competitive manner, with an IC50 of 26.4 nM, which is more potent than those of tacrine and huperzine A. Most importantly, we have shown, for the first time that A10E attenuated scopolamine-induced cognitive impairments without affecting motor function in mice. A10E effectively attenuated impairments of learning and memory to a similar extent as donepezil, an inhibitor of AChE used for treating Alzheimer’s disease (AD). In addition, A10E significantly decreased AChE activity in the brain of mice, suggesting that A10E might cross the brain blood-barrier. Taken together, our results demonstrated that A10E, a designed dual-binding AChE inhibitor, could effectively reverse cognitive impairments, indicating that A10E might provide therapeutic efficacy for AD treatment.