501. Aggravation by selective COX-1 and COX-2 inhibitors of dextran sulfate sodium (DSS)-induced colon lesions in rats.
- Author
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Okayama M, Hayashi S, Aoi Y, Nishio H, Kato S, and Takeuchi K
- Subjects
- Animals, Cardiovascular Diseases, Celecoxib, Colitis, Ulcerative chemically induced, Colitis, Ulcerative metabolism, Colon drug effects, Colon metabolism, Colon pathology, Cyclooxygenase 2 genetics, Dextran Sulfate toxicity, Dinoprostone biosynthesis, Disease Models, Animal, Gene Expression drug effects, Indomethacin therapeutic use, Male, Peroxidase metabolism, Plasma Substitutes toxicity, RNA, Messenger genetics, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Spectrophotometry, Treatment Outcome, Colitis, Ulcerative drug therapy, Cyclooxygenase 1 drug effects, Cyclooxygenase 2 drug effects, Cyclooxygenase Inhibitors therapeutic use, Pyrazoles therapeutic use, Sulfonamides therapeutic use
- Abstract
We examined the effect of cyclooxygenase (COX) inhibitors on dextran sulfate sodium (DSS)-induced ulcerative colitis in rats and investigated the role of COX isozymes in the pathogenesis of this model. Experimental colitis was induced by treatment with 2.5% DSS in drinking water for 6 days. Indomethacin (a nonselective COX inhibitor), SC-560 (a selective COX-1 inhibitor), or celecoxib (a selective COX-2 inhibitor) was given PO twice daily for 6 days, during the first 3 or last 3 days of the experimental period. Daily treatment with 2.5% DSS for 6 days caused damage to the colon, with a decrease in body weight gain and colon length as well as an increase of myeloperoxidase (MPO) activity. All COX inhibitors given for 6 days significantly worsened the severity of DSS-induced colonic damage with increased MPO activity. The aggravation was also observed by SC-560 given for the first 3 days or by celecoxib given for the last 3 days. The expression of COX-2 mRNA in the colon was upregulated on day 3 during DSS treatment, with significant increase of prostaglandin E(2) PGE(2) production. The PGE(2) content on day 3 during DSS treatment was inhibited by both indomethacin and SC-560, but not by celecoxib; on day 6 it was suppressed by both indomethacin and celecoxib, but not SC-560. These results suggest that endogenous prostaglandins (PGs) afford protection against colonic ulceration, yet the COX isozyme responsible for the production of PGs differs depending on the stage of ulceration; COX-1 in the early stage and COX-2 in the late stage.
- Published
- 2007
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