title: Silibinin inhibits acetylcholinesterase activity and amyloid β peptide aggregation: a dual-target drug for the treatment of Alzheimer's disease.
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.
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Songwei
authors.initials: S
authors.lastname: Duan
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Runxuan
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xincheng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Ruibang
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xueman
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Guangzhou Brain and Psychiatric Hospital, Guangzhou, China.
authors.forename: Xicui
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Key Lab of High Performance Computing of Guangdong Province, Guangzhou, China.
authors.forename: Shaoliang
authors.initials: S
authors.lastname: Fang
authors.affiliation: Research Center for Drug Discovery and Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: gu_huaiyu@yahoo.com.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Gu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors; D018891:Dentate Gyrus / Q000378:metabolism / Q000502:physiology; D005260:Female; D008297:Male; D008822:Mice, Transgenic; D020944:Silybum marianum / Q000737:chemistry; D009416:Nerve Regeneration / Q000187:drug effects; D008517:Phytotherapy; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D000077385:Silybin; D012838:Silymarin / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D012838:Silymarin; D000077385:Silybin
keywords: APP/PS1 transgenic mice; Acetylcholinesterase; Alzheimer's disease; Amyloid β protein; MD simulation; Memory deficits; Silibinin