期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 768, 期 -, 页码 96-107出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2015.10.037
关键词
Harmine; Memory; Acetylcholinesterase; Scopolamine; APP/PS1
资金
- Key Program of Joint Funds of the National Natural Science Foundation of China
- Xinjiang Uygur Autonomous Region of China [U1130303]
- National Nature Science Foundation of China [81173119]
- Key Project of Ministry of Science and Technology of China [2012ZX09103201-051]
- Program of Shanghai Subject Chief Scientist [13XD1403500]
- Shanghai Eastern Scholar Program [2013-59]
- Shanghai E-Research Institute of Bioactive Constituent in TCM plan
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.
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