RRC ID 51781
Author Arikawa M, Kakinuma Y, Noguchi T, Todaka H, Sato T.
Title Donepezil, an acetylcholinesterase inhibitor, attenuates LPS-induced inflammatory response in murine macrophage cell line RAW 264.7 through inhibition of nuclear factor kappa B translocation.
Journal Eur J Pharmacol
Abstract We have previously demonstrated that the pharmacotherapy with donepezil, an acetylcholinesterase inhibitor, suppresses cardiac remodeling in a mouse model of ischemic heart failure after myocardial infarction (MI). However, the precise mechanisms of the cardioprotective effect of donepezil have not been completely delineated. Because post-ischemic inflammation is a pathological key event in the cardiac remodeling process following MI, we investigated the hypothesis that donepezil acts as an inhibitor of inflammatory mediators. RAW 264.7 murine macrophage cells were pretreated with donepezil (100µM) prior to a pro-inflammatory stimulation by administration of lipopolysaccharide (LPS, 10ng/ml). Donepezil significantly reduced intra- and extracellular levels of various kinds of inflammatory mediators such as TNF-α, IL-1β, IL-2, IL-6 and IL-18 after the LPS stimulation, and attenuated LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB). These results indicate that donepezil possesses an anti-inflammatory property. However, the inhibitory effect of donepezil on the macrophage inflammatory responses was never reproduced by ACh, nor was disrupted by ACh receptor blockers. Moreover, other kinds of acetylcholinesterase inhibitors failed to inhibit the inflammatory responses in LPS-stimulated macrophage cells. These results suggest that a cholinergic anti-inflammatory pathway would not be involved in the anti-inflammatory effect of donepezil and that the specific characteristics of donepezil in suppressing the LPS-induced cytokine release and the NF-κB activation would be independent of its acetylcholinesterase inhibition. The present study showed that donepezil exerts an anti-inflammatory effect independently of acetylcholinesterase inhibitory action, thereby donepezil may contribute to cardioprotection during cardiac remodeling process in an ischemic heart failure after MI.
Volume 789
Pages 17-26
Published 2016-10-15
DOI 10.1016/j.ejphar.2016.06.053
PII S0014-2999(16)30423-X
PMID 27373848
MeSH Acetylcholinesterase / metabolism* Active Transport, Cell Nucleus / drug effects Animals Anti-Inflammatory Agents / pharmacology Cell Nucleus / drug effects* Cell Nucleus / metabolism Cell Survival / drug effects Cholinesterase Inhibitors / pharmacology* Cytokines / genetics Cytokines / metabolism Donepezil Gene Expression Regulation / drug effects Indans / pharmacology* Inflammation / chemically induced Inflammation / drug therapy Inflammation / metabolism Inflammation / pathology Lipopolysaccharides / pharmacology* Macrophages / drug effects* Mice NF-kappa B / metabolism* Piperidines / pharmacology* RAW 264.7 Cells
IF 3.17
Times Cited 19
Human and Animal Cells RAW 264(RCB0535)