A new class of COX-2 inhibitor, rutaecarpine from Evodia rutaecarpa.
OBJECTIVE
We investigated the effect of a new class of COX-2 inhibitor, rutaecarpine, on the production of PGD2 in bone marrow derived mast cells (BMMC) and PGE2 in COX-2 transfected HEK293 cells. Inflammation was induced by lambda-carrageenan in male Splague-Dawley (SD) rats.


METHODS
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 PGD2 and PGE2 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.


METHODS
Rutaecarpine and indomethacin dissolved in 0.1% carboxymethyl cellulose was administered intraperitoneally and, 1 h later, lambda-carrageenan solution was injected to right hind paw of rats. Paw volumes were measured using plethysmometer 5 h after lambda-carrageenan injection.


RESULTS
Rutaecarpine inhibited COX-2 and COX-1 dependent phases of PGD2 generation in BMMC in a concentration-dependent manner with an IC50 of 0.28 microM and 8.7 microM, respectively. It inhibited COX-2-dependent conversion of exogenous arachidonic acid to PGE2 in a dose-dependent manner by the COX-2-transfected HEK293 cells. However, rutaecarpine inhibited neither PLA2 and COX-1 activity nor COX-2 protein and mRNA expression up to the concentration of 30 microM in BMMC, indicating that rutaecarpine directly inhibited COX-2 activity. Furthermore, rutaecarpine showed in vivo anti-inflammatory activity on rat lambda-carrageenan induced paw edema by intraperitoneal administration.


CONCLUSIONS
Anti-inflammatory activity of Evodia rutaecarpa could be attributed at least in part by inhibition of COS-2.
Moon
T C
TC
College of Pharmacy, Yeungnam University, Gyongsan, Korea.
Murakami
M
M
Kudo
I
I
Son
K H
KH
Kim
H P
HP
Kang
S S
SS
Chang
H W
HW
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D005638:Fruit / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D026121:Indole Alkaloids; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D052999:Quinazolinones
D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D026121:Indole Alkaloids; D007527:Isoenzymes; D008565:Membrane Proteins; D010936:Plant Extracts; D011451:Prostaglandin-Endoperoxide Synthases; D011799:Quinazolines; C028632:rutecarpine; D052999:Quinazolinones; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat