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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity

Authors: Soraya Wilke Saliba, Ariel R. Marcotegui, Ellen Fortwängler, Johannes Ditrich, Juan Carlos Perazzo, Eduardo Muñoz, Antônio Carlos Pinheiro de Oliveira, Bernd L. Fiebich

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

N-arachidonoylphenolamine (AM404), a paracetamol metabolite, is a potent agonist of the transient receptor potential vanilloid type 1 (TRPV1) and low-affinity ligand of the cannabinoid receptor type 1 (CB1). There is evidence that AM404 exerts its pharmacological effects in immune cells. However, the effect of AM404 on the production of inflammatory mediators of the arachidonic acid pathway in activated microglia is still not fully elucidated.

Method

In the present study, we investigated the effects of AM404 on the eicosanoid production induced by lipopolysaccharide (LPS) in organotypic hippocampal slices culture (OHSC) and primary microglia cultures using Western blot, immunohistochemistry, and ELISA.

Results

Our results show that AM404 inhibited LPS-mediated prostaglandin E2 (PGE2) production in OHSC, and LPS-stimulated PGE2 release was totally abolished in OHSC if microglial cells were removed. In primary microglia cultures, AM404 led to a significant dose-dependent decrease in the release of PGE2, independent of TRPV1 or CB1 receptors. Moreover, AM404 also inhibited the production of PGD2 and the formation of reactive oxygen species (8-iso-PGF2 alpha) with a reversible reduction of COX-1- and COX-2 activity. Also, it slightly decreased the levels of LPS-induced COX-2 protein, although no effect was observed on LPS-induced mPGES-1 protein synthesis.

Conclusions

This study provides new significant insights about the potential anti-inflammatory role of AM404 and new mechanisms of action of paracetamol on the modulation of prostaglandin production by activated microglia.
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Metadata
Title
AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity
Authors
Soraya Wilke Saliba
Ariel R. Marcotegui
Ellen Fortwängler
Johannes Ditrich
Juan Carlos Perazzo
Eduardo Muñoz
Antônio Carlos Pinheiro de Oliveira
Bernd L. Fiebich
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1014-3

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