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Neurobiol Aging. 2015 May;36(5):1792-807. doi: 10.1016/j.neurobiolaging.2015.02.002. Epub 2015 Feb 11.

Silibinin inhibits acetylcholinesterase activity and amyloid β peptide aggregation: a dual-target drug for the treatment of Alzheimer's disease.

Author information

1
Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.
2
Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
3
Guangzhou Brain and Psychiatric Hospital, Guangzhou, China.
4
Key Lab of High Performance Computing of Guangdong Province, Guangzhou, China.
5
Research Center for Drug Discovery and Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
6
Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: gu_huaiyu@yahoo.com.

Abstract

Alzheimer's disease (AD) is characterized by amyloid β (Aβ) peptide aggregation and cholinergic neurodegeneration. Therefore, in this paper, we examined silibinin, a flavonoid extracted from Silybum marianum, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aβ peptide aggregation for AD treatment. To achieve this, we used molecular docking and molecular dynamics simulations to examine the affinity of silibinin with Aβ and AChE in silico. Next, we used circular dichroism and transmission electron microscopy to study the anti-Aβ aggregation capability of silibinin in vitro. Moreover, a Morris Water Maze test, enzyme-linked immunosorbent assay, immunohistochemistry, 5-bromo-2-deoxyuridine double labeling, and a gene gun experiment were performed on silibinin-treated APP/PS1 transgenic mice. In molecular dynamics simulations, silibinin interacted with Aβ and AChE to form different stable complexes. After the administration of silibinin, AChE activity and Aβ aggregations were down-regulated, and the quantity of AChE also decreased. In addition, silibinin-treated APP/PS1 transgenic mice had greater scores in the Morris Water Maze. Moreover, silibinin could increase the number of newly generated microglia, astrocytes, neurons, and neuronal precursor cells. Taken together, these data suggest that silibinin could act as a dual inhibitor of AChE and Aβ peptide aggregation, therefore suggesting a therapeutic strategy for AD treatment.

KEYWORDS:

APP/PS1 transgenic mice; Acetylcholinesterase; Alzheimer's disease; Amyloid β protein; MD simulation; Memory deficits; Silibinin

[Indexed for MEDLINE]

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