title: Diacerein is a potent and selective inhibitor of palmitoylethanolamide inactivation with analgesic activity in a rat model of acute inflammatory pain.
abstract: Palmitoylethanolamide (PEA) is produced by mammalian cells from its biosynthetic precursor, N-palmitoyl-phosphatidyl-ethanolamine, and inactivated by enzymatic hydrolysis to palmitic acid and ethanolamine. Apart from fatty acid amide hydrolase (FAAH), the N-acylethanolamine-hydrolyzing acid amidase (NAAA), a lysosomal enzyme, was also shown to catalyze the hydrolysis of PEA and to limit its analgesic and anti-inflammatory action. Here we report the finding of a new potential inhibitor of NAAA, EPT4900 (4,5-diacetyloxy-9,10-dioxo-anthracene-2-carboxylic acid, diacerein). EPT4900 exhibited a high inhibitory activity on human recombinant NAAA over-expressed in HEK293 cells (HEK-NAAA cells). EPT4900 selectively increased the levels of PEA in intact HEK-NAAA cells, and inhibited inflammation as well as hyperalgesia in rats treated with an intraplantar injection of carrageenan. This latter effect was accompanied by elevation of PEA endogenous levels in the paw skin.
authors.affiliation: Epitech Group S.r.l., Saccolongo, PD, Italy; Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, C.N.R., Pozzuoli, NA, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.affiliation: Dipartimento di Scienze Biologiche ed Ambientali, Università di Messina, Italy.
authors.forename: Akbar
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Epitech Group S.r.l., Saccolongo, PD, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Marcolongo
authors.affiliation: Dipartimento di Scienze Biologiche ed Ambientali, Università di Messina, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.affiliation: Epitech Group S.r.l., Saccolongo, PD, Italy; Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, C.N.R., Pozzuoli, NA, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.affiliation: Epitech Group S.r.l., Saccolongo, PD, Italy; Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, C.N.R., Pozzuoli, NA, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Verde
authors.affiliation: Dipartimento di Scienze Biologiche ed Ambientali, Università di Messina, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, C.N.R., Pozzuoli, NA, Italy. Electronic address: vdimarzo@icb.cnr.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002351:Carrageenan; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000378:metabolism
chemical_list: D000577:Amides; D000700:Analgesics; D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D004983:Ethanolamines; D010169:Palmitic Acids; C025292:diacerein; C005958:palmidrol; D002351:Carrageenan; D000581:Amidohydrolases; C523108:NAAA protein, human
keywords: Diacerein; Inflammation; NAAA; Palmitoylethanolamide