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.
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.
authors.affiliation: Department of Natural Science, Faculty of Science, Kochi University, Akebono, Kochi, Japan; Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi, Japan. Electronic address: marikawa@kochi-u.ac.jp.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Arikawa
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kakinuma
authors.affiliation: Department of Cardiology, Neurology and Aging Science, Kochi Medical School, Nankoku, Kochi, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Todaka
authors.affiliation: Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sato
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000077265:Donepezil; D005786:Gene Expression Regulation / Q000187:drug effects; D007189:Indans / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D000067996:RAW 264.7 Cells
chemical_list: D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; D016207:Cytokines; D007189:Indans; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase
keywords: Anti-inflammation; Cardiac remodeling; Cardioprotection; Non-neuronal cholinergic system; Post-ischemic inflammation