title: N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2.
abstract: Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E2(PGE2) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE2production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.
authors.forename: Ya
authors.identifier: 0000-0002-8886-9936
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Chemical Technologies, University of Calabria , 87036 Cosenza, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Plastina
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vincken
authors.forename: Renate
authors.initials: R
authors.lastname: Jansen
authors.forename: Michiel
authors.initials: M
authors.lastname: Balvers
authors.affiliation: Research Centre Technology & Innovation, Innovative Testing in Life Sciences and Chemistry, University of Applied Sciences , 3584 CH Utrecht, The Netherlands.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Ten Klooster
authors.forename: Harry
authors.initials: H
authors.lastname: Gruppen
authors.forename: Renger
authors.initials: R
authors.lastname: Witkamp
authors.forename: Jocelijn
authors.initials: J
authors.lastname: Meijerink
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C520236:N-docosahexaenoyl dopamine; D016328:NF-kappa B; D012333:RNA, Messenger; D004281:Docosahexaenoic Acids; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D004298:Dopamine
keywords: Endocannabinoids; N-arachidonoyl dopamine; N-docosahexaenoyl dopamine; cyclooxygenase-2; interleukin-6; prostaglandin E2