title: Anti-inflammatory and analgesic activity of a novel inhibitor of microsomal prostaglandin E synthase-1 expression.
abstract: In a previous study, we reported a new gamma-hydroxybutenolide derivative, 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH), as inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) expression in lypopolysaccharide (LPS) stimulated RAW 264.7 and TPH-1 cells, without affecting cyclooxygenase-2 (COX-2). In this study, we evaluated the in vivo effect of BTH on some acute and chronic inflammatory animal models in relation to its inhibitory profile on mPGES-1 expression. In the zymosan-induced mouse air pouch model, BTH produced a dose-dependent inhibition of prostaglandin E(2) (PGE(2)) production and mPGES-1 protein expression in pouch exudates without any effect on COX-2 protein expression. This behavior was confirmed in the chronic model of collagen-induced arthritis, where administration of BTH (5 mg/kg) clearly reduced PGE(2) and mPGES-1 expression in joint tissues, whereas COX-2 was unaffected. These effects were accompanied by the suppression of clinical and histopathological manifestations of disease such as the loss of proteoglycan, and the destruction of surface cartilage. Other enzymes participating in the metabolism of arachidonic acid, such as prostaglandin I(2) synthase, tromboxane A(2) synthase or 5-lipoxygenase were unaffected by this compound. The acetic acid-induced hyperalgesia model in LPS-sensitized mice showed a dose-dependent analgesic effect of BTH, exerting an ED(50) value of 6.2 mg/kg. Our data suggest that inhibition of mPGES-1 protein expression in acute and chronic inflammatory models by BTH, could provide a potential therapeutic target and a pharmacological tool to discern the role of the inducible enzymes COX-2 and mPGES-1 in inflammatory pathologies.
authors.affiliation: Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Av Vicent Andrés Estellés s/n, Burjassot, Valencia, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Guerrero
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aquino
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Terencio
authors.forename: Miguel
authors.initials: M
authors.lastname: Payá
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000085:Acetates / Q000633:toxicity; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002908:Chronic Disease; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000378:metabolism
chemical_list: C520645:4-benzo(b)thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one; D000085:Acetates; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D013876:Thiophenes; D007975:Leukotriene B4; D013929:Thromboxane B2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015107:4-Butyrolactone