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 immun...
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-017-1014-3 |
| _version_ | 1828760385973387264 |
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| author | Soraya Wilke Saliba Ariel R. Marcotegui Ellen Fortwängler Johannes Ditrich Juan Carlos Perazzo Eduardo Muñoz Antônio Carlos Pinheiro de Oliveira Bernd L. Fiebich |
| author_facet | Soraya Wilke Saliba Ariel R. Marcotegui Ellen Fortwängler Johannes Ditrich Juan Carlos Perazzo Eduardo Muñoz Antônio Carlos Pinheiro de Oliveira Bernd L. Fiebich |
| author_sort | Soraya Wilke Saliba |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T01:13:05Z |
| format | Article |
| id | doaj.art-dece29d9a99c41a1ac18844da0b47c18 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T01:13:05Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-dece29d9a99c41a1ac18844da0b47c182022-12-22T01:25:59ZengBMCJournal of Neuroinflammation1742-20942017-12-0114111110.1186/s12974-017-1014-3AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activitySoraya Wilke Saliba0Ariel R. Marcotegui1Ellen Fortwängler2Johannes Ditrich3Juan Carlos Perazzo4Eduardo Muñoz5Antônio Carlos Pinheiro de Oliveira6Bernd L. Fiebich7Department of Psychiatry and Psychotherapy, Laboratory of Translational Psychiatry, Faculty of Medicine, Medical Center – University of FreiburgLaboratory of Hepatic Encephalopathy and Portal Hypertension, Center of Applied and Experimental Pathology, University of Buenos AiresDepartment of Psychiatry and Psychotherapy, Laboratory of Translational Psychiatry, Faculty of Medicine, Medical Center – University of FreiburgDepartment of Psychiatry and Psychotherapy, Laboratory of Translational Psychiatry, Faculty of Medicine, Medical Center – University of FreiburgLaboratory of Hepatic Encephalopathy and Portal Hypertension, Center of Applied and Experimental Pathology, University of Buenos AiresDepartamento de Biología Celular, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Fisiología e Inmunología, Universidad de CórdobaDepartment of Pharmacology, Universidade Federal de Minas GeraisDepartment of Psychiatry and Psychotherapy, Laboratory of Translational Psychiatry, Faculty of Medicine, Medical Center – University of FreiburgAbstract 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.http://link.springer.com/article/10.1186/s12974-017-1014-3AM404AcetaminophenMicrogliaInflammationProstaglandinsCyclooxygenase |
| spellingShingle | Soraya Wilke Saliba Ariel R. Marcotegui Ellen Fortwängler Johannes Ditrich Juan Carlos Perazzo Eduardo Muñoz Antônio Carlos Pinheiro de Oliveira Bernd L. Fiebich AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity Journal of Neuroinflammation AM404 Acetaminophen Microglia Inflammation Prostaglandins Cyclooxygenase |
| title | AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity |
| title_full | AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity |
| title_fullStr | AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity |
| title_full_unstemmed | AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity |
| title_short | AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity |
| title_sort | am404 paracetamol metabolite prevents prostaglandin synthesis in activated microglia by inhibiting cox activity |
| topic | AM404 Acetaminophen Microglia Inflammation Prostaglandins Cyclooxygenase |
| url | http://link.springer.com/article/10.1186/s12974-017-1014-3 |
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