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

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.MethodIn 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.ResultsOur 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1014-3) contains supplementary material, which is available to authorized users.

Lead (Pb) as a Factor Initiating and Potentiating Inflammation in Human THP-1 Macrophages

“…Its increased expression have been shown in the microglia cells located around amyloid plaques in the post-mortem brains of patients with AD [39,40]. Activated microglia secrete an array of pro-inflammatory factors, such as prostaglandins, whose accumulation contributes to neuronal damages [41][42][43]. Alzheimer s disease patients brains also exhibit an increased expression of COX-2 [44][45][46], which through its effect on total amyloid precursor proteins (APP) is correlated with the severity of brain amyloid plaque pathology [44].…”

Repurposing Antibacterial AM404 As a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells

“…Our understanding of the molecular pathways and links between inflammation and cancer is continuously improving. AM404 is currently being studied for its antibacterial and anti-inflammatory effects notably for reducing the production of IL-1β, IL-6 as well as decreasing oxidative stress and for their association with circulating tumour necrosis factor (TNF)-α [19]. Previously, AM0404 has been reported to inhibit NF-κB and NFAT activation on neuroblastoma and glioma cells.…”

“…AM404 is a metabolite of acetaminophen with antibacterial activity, also known as N-arachidonoylphenolamine with a chemical formula of C 26 H 37 NO 2 [19]. Acetaminophen (N-acetyl-para-aminophenol or paracetamol) is one of the most commonly used over-the-counter drugs for its analgesic and antipyretic properties [20].…”

“…Acetaminophen undergoes de-acetylation to p-aminophenol in both liver and nervous system and p-aminophenol is conjugated with arachidonic acid to produce AM404 in the nervous system. It has been suggested that AM404 may be responsible for the analgesic mechanism of paracetamol [19]. Some studies have demonstrated AM404s antibacterial and anti-inflammatory effects in reducing oxidative stress are associated with the presence of the phenolic group in its structure ( Figure 1A) [19,22,23].…”

“…It has been suggested that AM404 may be responsible for the analgesic mechanism of paracetamol [19]. Some studies have demonstrated AM404s antibacterial and anti-inflammatory effects in reducing oxidative stress are associated with the presence of the phenolic group in its structure ( Figure 1A) [19,22,23]. Currently, there is no established data available for AM404 in colorectal cancer.…”