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Slattery et al. Neuroimmunol Neuroinflammation 2018;5:11 Neuroimmunology
DOI: 10.20517/2347-8659.2018.05 and Neuroinflammation

Original Article Open Access

Acetaminophen metabolites p-aminophenol and
AM404 inhibit microglial activation

Wyatt T. Slattery, Andis Klegeris

Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC V1V 1V7, Canada.
Correspondence to: Dr. Andis Klegeris, Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC
V1V 1V7, Canada. E-mail: andis.klegeris@ubc.ca

How to cite this article: Slattery WT, Klegeris A. Acetaminophen metabolites p-aminophenol and AM404 inhibit microglial
activation. Neuroimmunol Neuroinflammation 2018;5:11. http://dx.doi.org/10.20517/2347-8659.2018.05

Received: 17 Feb 2018 First Decision: 16 Mar 2018 Revised: 22 Mar 2018 Accepted: 26 Mar 2018 Published: 12 Apr 2018
Science Editor: Athanassios P. Kyritsis Copy Editor: Jun-Yao Li Production Editor: Cai-Hong Wang

Abstract
Aim: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, deposits of amyloid
beta and neurofibrillary tangles. Inflammation facilitated by microglia, the resident immune cells of the brain, contribute
to the pathogenesis of AD. Epidemiological data indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), which
are cyclooxygenase (COX) inhibitors, reduce the risk of developing AD when administered over the course of two or
more years. The mechanisms underlying this protective effect are unknown. Acetaminophen (paracetamol), which is
not effective as an inhibitor of COX in peripheral tissues, may provide similar protection without the adverse effects
of chronic NSAID use. The beneficial effects of acetaminophen have been proposed to stem from its metabolites
p-aminophenol and N-arachidonoylaminophenol (AM404), of which, AM404 possesses analgesic and antipyretic
properties. The goal of this study was to compare the effects of acetaminophen and its metabolites on microglial
immune function and to elucidate the molecular mechanisms engaged by these compounds.

Methods: Lipopolysaccharide-stimulated BV-2 murine microglia were used as models. Microglial activation was
monitored by their secretion of nitric oxide.

Results: P-aminophenol and AM404 suppressed nitric oxide secretion from stimulated microglia more effectively than
acetaminophen through pathways that were independent of COX inhibition, cannabinoid receptor type two (CB2)
inhibition, and activation of transient receptor potential cation channel subfamily V member 1 (TRPV1).

Conclusion: Since AM404 has been previously demonstrated to attenuate NF-kB activation, it is likely that
the protective effects of acetaminophen against adverse microglia activation are mediated by its metabolites
p-aminophenol and AM404 inhibiting this transcription factor.

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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