A new class of COX-2 inhibitor, rutaecarpine from Evodia rutaecarpa

초록

Objective and Design: We investigated the effect of a new class of COX-2 inhibitor, rutaecarpine, on the production of PGD<inf>2</inf> in bone marrow derived mast cells (BMMC) and PGE<inf>2</inf> in COX-2 transfected HEK293 cells. Inflammation was induced by λ-carrageenan in male Splague-Dawley (SD) rats. Material: Rutaecarpine (8,13-Dihydroindolo[2',3':3,4]pyridol[2,1-b]quinazolin-5(7H)- one) was isolated from the fruits of Evodia rutaecarpa. BMMC were cultured with WEHI-3 conditioned medium. c-Kit ligand and IL-10 were obtained by their expression in baculovirus. Methods: The generation of PGD<inf>2</inf> and PGE<inf>2</inf> were determined by their assay kit. COX-1 and COX-2 protein and mRNA expression was determined by BMMC in the presence of KL, LPS and IL-10. Treatment: Rutaecarpine and indomethacin dissolved in 0.1% carboxymethyl cellulose was administered intraperitoneally and, 1 h later, λ-carrageenan solution was injected to right hind paw of rats. Paw volumes were measured using plethysmometer 5 h after λ-carrageenan injection. Results: Rutaecarpine inhibited COX-2 and COX-1 dependent phases of PGD<inf>2</inf> generation in BMMC in a concentration-dependent manner with an IC<inf>50</inf> of 0.28 μM and 8.7 μM, respectively. It inhibited COX-2-dependent conversion of exogenous arachidonic acid to PGE<inf>2</inf> in a dose-dependent manner by the COX-2-transfected HEK293 cells. However, rutaecarpine inhibited neither PLA<inf>2</inf> and COX-1 activity nor COX-2 protein and mRNA expression up to the concentration of 30 μM in BMMC, indicating that rutaecarpine directly inhibited COX-2 activity. Furthermore, rutaecarpine showed in vivo anti-inflammatory activity on rat λ-carrageenan induced paw edema by intraperitoneal administration. Conclusion: Anti-inflammatory activity of Evodia rutaecarpa could be attributed at least in part by inhibition of COS-2.

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