Aggravation by Selective COX-1 and COX-2 Inhibitors of Dextran Sulfate Sodium (DSS)-Induced Colon Lesions in Rats |
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Authors: | Mitsuaki Okayama Shusaku Hayashi Yoko Aoi Hikaru Nishio Shinichi Kato Koji Takeuchi |
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Affiliation: | (1) Department of Pharmacology and Experimental Therapeutics Kyoto Pharmaceutical University, Misasagi, Yamashina Kyoto, 607-8414, Japan |
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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 E2 PGE2 production. The PGE2 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. |
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Keywords: | Dextran sulfate sodium-induced colon lesion Nonsteroidal anti-inflammatory drug Prostaglandin Cyclooxygenase (COX) Selective COX-1 and COX-2 inhibitors |
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