Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice

Inanaga, Keita; Ichiki, Toshihiro; Miyazaki, Ryohei; Takeda, Kotaro; Hashimoto, Toru; Matsuura, Hirohide; Sunagawa, Kenji

doi:10.1016/j.atherosclerosis.2010.07.027

Cited by 31 publications

(18 citation statements)

References 28 publications

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“…In this study, the dose of donepezil administrated to rats was 5.0 mg/kg/day, which was about 50 times higher than the therapeutic doses used in the clinical setting. However, although different from that used in humans, a daily dose of 5.0 mg/kg has been extensively used in animal studies without any side effects [13,23]. In a preliminary study, we confirmed that this dose of donepezil was the submaximal dose that did not cause side effects such as vomiting, diarrhea, anorexia, or growth retardation.…”

Section: Discussionsupporting

confidence: 70%

Donepezil, Therapeutic Acetylcholinesterase Inhibitor, Prevents the Progression of Ventricular Dysfunction by Promoting Myocardial Glucose Utilization in Rat Model of Chronic Heart Failure Following Myocardial Infarction

Arikawa¹,

Kakinuma²,

Nakatani³

et al. 2014

Cardiol Pharmacol

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Section: Discussionsupporting

confidence: 70%

Donepezil, Therapeutic Acetylcholinesterase Inhibitor, Prevents the Progression of Ventricular Dysfunction by Promoting Myocardial Glucose Utilization in Rat Model of Chronic Heart Failure Following Myocardial Infarction

Arikawa¹,

Kakinuma²,

Nakatani³

et al. 2014

Cardiol Pharmacol

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“…In ATH, perhaps surprisingly, donepezil infusion could attenuate atherogenesis in susceptible mice [279]. …”

Section: Discussionmentioning

confidence: 99%

Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

2014

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BackgroundAging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology?DiscussionBoth ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology.MechanismInfection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of ‘immunosterol’ 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease.SummaryWe postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

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“…Donepezil, another centrally acting and FDA-approved acetylcholinesterase inhibitor, suppresses CCL2 and TNF expression, attenuates athero-sclerosis and improves long-term survival following chronic heart failure in rodents. 120,121 These findings suggest that centrally acting acetylcholinesterase inhibitors could potentially be developed for the treatment of atherosclerosis.…”

Section: Therapeutic Implicationsmentioning

confidence: 93%

The vagus nerve and the inflammatory reflex—linking immunity and metabolism

2012

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The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.

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Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice

Abstract: The present study revealed novel anti-oxidative and anti-atherosclerotic effects of pharmacological stimulation of cholinergic system by donepezil. Donepezil may be used as a novel therapeutics for the atherosclerotic cardiovascular diseases.

Cited by 31 publications

References 28 publications

Donepezil, Therapeutic Acetylcholinesterase Inhibitor, Prevents the Progression of Ventricular Dysfunction by Promoting Myocardial Glucose Utilization in Rat Model of Chronic Heart Failure Following Myocardial Infarction

Donepezil, Therapeutic Acetylcholinesterase Inhibitor, Prevents the Progression of Ventricular Dysfunction by Promoting Myocardial Glucose Utilization in Rat Model of Chronic Heart Failure Following Myocardial Infarction

Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

The vagus nerve and the inflammatory reflex—linking immunity and metabolism

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