title: Characterization of a new mPGES-1 inhibitor in rat models of inflammation.
abstract: Microsomal prostaglandin E synthase (mPGES)-1 inhibition has been proposed as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. This novel approach could potentially mitigate the gastro-intestinal and cardiovascular side effects seen after long-term treatment with traditional non-steroidal anti-inflammatory drugs (NSAIDs) and Coxibs respectively. Several human mPGES-1 inhibitors have been developed in the recent years. However, they were all shown to be considerably less active on rodent mPGES-1, precluding the study of mPGES-1 inhibition in rodent models of inflammation and pain. The aim of this study was to characterize the new mPGES-1 inhibitor compound II, a pyrazolone that has similar potency on rat and human recombinant mPGES-1, in experimental models of inflammation. In cell culture, compound II inhibited PGE2 production in synovial fibroblasts from patients with rheumatoid arthritis (RASF) and in rat peritoneal macrophages. In vivo, compound II was first characterized in the rat air pouch model of inflammation where treatment inhibited intra-pouch PGE2 production. Compound II was also investigated in a rat adjuvant-induced arthritis model where it attenuated both the acute and delayed inflammatory responses. In conclusion, compound II represents a valuable pharmacological tool for the study of mPGES-1 inhibition in rat models.
authors.affiliation: Department of Medicine, Rheumatology Research Unit, Karolinska Institutet, S-171 77, Stockholm, Sweden. Patrick.Leclerc@ki.se
authors.forename: Patrick
authors.initials: P
authors.lastname: Leclerc
authors.forename: Sven-Christian
authors.initials: SC
authors.lastname: Pawelzik
authors.forename: Helena
authors.initials: H
authors.lastname: Idborg
authors.forename: Linda
authors.initials: L
authors.lastname: Spahiu
authors.forename: Charlotte
authors.initials: C
authors.lastname: Larsson
authors.forename: Patric
authors.initials: P
authors.lastname: Stenberg
authors.forename: Marina
authors.initials: M
authors.lastname: Korotkova
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010146:Pain / Q000188:drug therapy / Q000473:pathology; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D047069:Pyrazolones / Q000008:administration & dosage*; D051381:Rats; D013582:Synovial Fluid / Q000187:drug effects / Q000201:enzymology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D047069:Pyrazolones; C038362:pyrazolone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000071876:Prostaglandin-E Synthases; C497818:Ptges protein, rat; D015232:Dinoprostone