title: The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice.
abstract: Donepezil is a potent and selective acetylcholinesterase inhibitor. It has been reported to restore cognitive performance in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. However, there are no reports about the anti-inflammatory effects of donepezil on EAE. In this study, the donepezil treatments on EAE mice were initiated at day 7 post immunization (7 p.i., subclinical periods, early donepezil treatment) and day 13 p.i. (clinical periods, late donepezil treatment) with the dosage of 1, 2 and 4 mg/kg/d respectively and the treatments persisted throughout the experiments. Blood-brain barrier (BBB) permeability was detected by Evan's blue content, the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, Akt and phosphorylated Akt (p-Akt) as well as nerve growth factor (NGF) and its precursor form (proNGF) in the brains of EAE mice were detected by Western blot, and the levels of interferon-γ and interleukin-4 in the splenocytes culture supernatants and brains of EAE mice were evaluated by ELISA. The results showed that the 2 mg/kg/d late donepezil treatment was the optimal dosage and could ameliorate clinical and pathological parameters, improve magnetic resonance imaging outcomes, reduce the permeability of BBB, inhibit the production of MMP-2 and MMP-9, modulate the expression of NGF and proNGF, increase Th2 bias and the phosphorylation of Akt in the brains of EAE mice. Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezil's neuroprotective activities in MS.
authors.affiliation: Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.forename: Shaoqiong
authors.initials: S
authors.lastname: Chen
authors.forename: Cansheng
authors.initials: C
authors.lastname: Zhu
authors.forename: Aimin
authors.initials: A
authors.lastname: Wu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Liu
authors.forename: Lili
authors.initials: L
authors.lastname: Ma
authors.forename: Dongliang
authors.initials: D
authors.lastname: Zhu
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Ma
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Kang
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Pi
authors.forename: Fuhua
authors.initials: F
authors.lastname: Peng
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005070:Evans Blue / Q000378:metabolism; D005260:Female; D007189:Indans / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000096:biosynthesis; D010766:Phosphorylation; D010880:Piperidines / Q000627:therapeutic use*; D011498:Protein Precursors / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; D007189:Indans; D010880:Piperidines; D011498:Protein Precursors; C489226:pro-nerve growth factor, mouse; D015847:Interleukin-4; D005070:Evans Blue; D007371:Interferon-gamma; D000077265:Donepezil; D020932:Nerve Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Anti-inflammatory effect; Blood–brain barrier; Donepezil; Experimental autoimmune encephalomyelitis; Interferon-γ; Interleukin-4; Matrix metalloproteinase-2; Matrix metalloproteinase-9; Nerve growth factor