title: Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation.
abstract: Identifying points of control in inflammation is essential to discovering safe and effective antiinflammatory medicines. Palmitoylethanolamide (PEA) is a naturally occurring lipid amide that, when administered as a drug, inhibits inflammatory responses by engaging peroxisome proliferator-activated receptor-alpha (PPAR-alpha). PEA is preferentially hydrolyzed by the cysteine amidase N-acylethanolamine-hydrolyzing acid amidase (NAAA), which is highly expressed in macrophages. Here we report the discovery of a potent and selective NAAA inhibitor, N-[(3S)-2-oxo-3-oxetanyl]-3-phenylpropanamide [(S)-OOPP], and show that this inhibitor increases PEA levels in activated leukocytes and blunts responses induced by inflammatory stimuli both in vitro and in vivo. These effects are stereoselective, mimicked by exogenous PEA, and abolished by PPAR-alpha deletion. (S)-OOPP also attenuates inflammation and tissue damage and improves recovery of motor function in mice subjected to spinal cord trauma. The results suggest that PEA activation of PPAR-alpha in leukocytes serves as an early stop signal that contrasts the progress of inflammation. The PEA-hydrolyzing amidase NAAA may provide a previously undescribed target for antiinflammatory medicines.
authors.affiliation: Department of Pharmacology, University of California, Irvine, CA 92697-4624, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.forename: Chenggang
authors.initials: C
authors.lastname: Zhu
authors.forename: Natalia
authors.initials: N
authors.lastname: Battista
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonietti
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002351:Carrageenan; D020134:Catalytic Domain; D002465:Cell Movement / Q000187:drug effects; D055808:Drug Discovery; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004983:Ethanolamines; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D047493:PPAR alpha / Q000819:agonists; D010169:Palmitic Acids / Q000378:metabolism*; D010666:Phenylpropionates / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000201:enzymology / Q000473:pathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D000893:Anti-Inflammatory Agents; D002087:Butyrates; D002351:Carrageenan; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; D010666:Phenylpropionates; D010671:Phenylurea Compounds; D000099252:Fatty Acid Amide Hydrolases; C453899:GW 7647; C005958:palmidrol