Alimentary TractCyclooxygenase 1 contributes to inflammatory responses in rats and mice: Implications for gastrointestinal toxicity☆,☆☆,★
Section snippets
Animals
Male Wistar rats weighing 200–225 g were obtained from Charles River Breeding Farms Ltd. (Montreal, Quebec, Canada) and were housed in plastic-bottom cages and fed standard pelleted chow and water ad libitum. Male and female mice in which the gene for COX-2 gene had been disrupted (B6,129-Ptgs2tm1jed) and normal, wild-type siblings weighing 18–22 g were obtained from The Jackson Laboratory (Bar Harbor, ME). These mice have been described in detail previously.17 The mice were housed in
Studies in rats
Injection of carrageenan into the footpad of the rat caused a progressive increase in paw volume (to ~160% of the original volume), with peak levels reached at 4 hours. This response was inhibited by as much as 70% by the test drugs at the doses tested. The reduction of edema by the five test drugs is summarized in Figure 1A, which shows the area under the curve data for each compound.
Discussion
Since the identification of COX-2 in 1991,21 there has been an enormous effort to develop drugs that would selectively inhibit this isoform, sparing COX-1. It has been suggested that the PGs that contribute to inflammatory processes are derived exclusively from COX-2, so selective COX-2 inhibitors would exhibit the same anti-inflammatory and analgesic effects as standard NSAIDs but would spare the gastrointestinal tract of injury.3, 4, 5 The findings of the present study raise a number of
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2021, Bioorganic and Medicinal ChemistryCitation Excerpt :On 5th day of chronic model, % inhibition of edema was obtained as 54% and 63% for 10b and 10c, respectively. Celecoxib (selective COX-2 inhibitor) was used as a standard drug because COX-2 is a major contributor to prostanoid synthesis in chronic phase of inflammation.17–19 Celecoxib was found to inhibit 68% of rat paw edema as given in Table 2.
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Address requests for reprints to: John L. Wallace, Ph.D., Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, T2N 4N1, Canada. e-mail: [email protected]; fax: (403) 270-3353.
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Supported by a clinical fellowship from the Alberta Heritage Foundation for Medical Research (AHFMR) (to A.B.) and a studentship (to S.A.) and grants from the Medical Research Council of Canada (MRC).
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Dr. Wallace is an MRC of Canada Senior Scientist and an AHFMR Scientist. Dr. Sharkey is an AHFMR Senior Scholar. Dr. MacNaughton is an AHFMR Scholar.