title: Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA) identifies novel bioactive signals.
abstract: Neuroinflammation and traumatic brain injury involve activation of inflammatory cells and production of local pro-inflammatory mediators that can amplify tissue damage. Using LC-UV-MS-MS-based lipidomics in tandem with functional screening at the single-cell level in microfluidic chambers, we identified a series of novel bioactive oxygenated docosahexaenoyl ethanolamide- (DHEA) derived products that regulated leukocyte motility. These included 10,17-dihydroxydocosahexaenoyl ethanolamide (10,17-diHDHEA) and 15-hydroxy-16(17)-epoxy-docosapentaenoyl ethanolamide (15-HEDPEA), each of which was an agonist of recombinant CB2 receptors with EC(50) 3.9 × 10(-10) and 1.0 × 10(-10) M. In human whole blood, 10,17-diHDHEA and 15-HEDPEA at concentrations as low as 10 pM each prevented formation of platelet-leukocyte aggregates involving either platelet-monocyte or platelet-polymorphonuclear leukocyte. In vivo, 15-HEDPEA was organ-protective in mouse reperfusion second organ injury. Together these results indicate that DHEA oxidative metabolism produces potent novel molecules with anti-inflammatory and organ-protective properties.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnamoorthy
authors.forename: Nitin
authors.initials: N
authors.lastname: Agrawal
authors.forename: Daniel
authors.initials: D
authors.lastname: Irimia
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D000577:Amides; D000818:Animals; D000893:Anti-Inflammatory Agents; D001773:Blood Cells / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006801:Humans; D007962:Leukocytes; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D044085:Microfluidics; D016877:Oxidants; D010973:Platelet Adhesiveness / Q000187:drug effects; D020011:Protective Agents; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D053719:Tandem Mass Spectrometry
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D016877:Oxidants; D020011:Protective Agents; D043885:Receptor, Cannabinoid, CB2; D004281:Docosahexaenoic Acids; C067518:4,7,10,13,16,19-docosahexaenoic acid ethyl ester