Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice
Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice
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DOI：
10.1016/j.ejphar.2015.10.037
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发表时间：
2015-12-05
影响因子：
5
通讯作者：
Wang, Changhong
中科院分区：
文献类型：
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作者：
He, Dandan;Wu, Hui;Wang, Changhong
骆驼蓬碱是骆驼蓬中的一种β-咔啉生物碱，具有广泛的药理活性，在体外对乙酰胆碱酯酶有很强的抑制作用。然而，它是否能挽救受损的认知功能尚未阐明。本研究采用Morris水迷宫实验，观察了其对东莨菪碱所致小鼠记忆障碍和阿尔茨海默病模型之一的APP/PS 1转基因小鼠的影响。此外，还考察了去氢骆驼蓬碱是否能穿透血脑屏障，与乙酰胆碱酯酶相互作用并抑制，激活下游信号网络。结果表明，去氢骆驼蓬碱（20 mg/kg）灌胃2周可有效地提高腹腔注射东莨菪碱（1 mg/kg）造成的C57 BL 16小鼠空间认知障碍。同时，长期食用骆驼蓬碱（20 mg/kg）10周也对APP/PS1小鼠受损的记忆力略有改善。此外，去氢骆驼蓬碱灌胃后即刻可通过血脑屏障进入脑实质，并调节Egr-1、c-Jun和c-Fos的表达。通过分子对接实验发现去氢骆驼蓬碱分子可以直接对接到乙酰胆碱酯酶的催化活性位点上，其体内抑制乙酰胆碱酯酶的活性部分证实了这一点。以上结果提示，去氢骆驼蓬碱可通过抑制乙酰胆碱酯酶活性，增强胆碱能神经传递，从而改善记忆障碍，为临床治疗乙酰胆碱酯酶缺乏性神经系统疾病提供了可能。(C)2015 Elsevier By. All rights reserved.
Harmine, a beta-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that harmine (20 mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL16 mice impaired by intraperitoneal injection of scopolamine (1 mg/kg). Meanwhile, long-term consumption of harmine (20 mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency. (C) 2015 Elsevier By. All rights reserved.