Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats. Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 mu g/kg) was given orally just before the indomethacin administration. The ulcer index induced by indomethacin was significantly (> 50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 mu g/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected. We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.
机构:
NYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
NYU, Grossman Sch Med, Div Translat Med, New York, NY USANYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
Friedman, Benjamin
Larranaga-Vera, Ane
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NYU, Grossman Sch Med, Div Translat Med, New York, NY USANYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
Larranaga-Vera, Ane
Castro, Cristina M.
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NYU, Grossman Sch Med, Div Translat Med, New York, NY USANYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
Castro, Cristina M.
Corciulo, Carmen
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NYU, Grossman Sch Med, Div Translat Med, New York, NY USANYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
Corciulo, Carmen
Rabbani, Piul
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NYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
NYU, Grossman Sch Med, Hansjorg Wyss Dept Plast Surg, New York, NY USANYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
Rabbani, Piul
Cronstein, Bruce N.
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NYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
NYU, Grossman Sch Med, Div Translat Med, New York, NY USA
NYU, Grossman Sch Med, Div Rheumatol, 435 East 30th St,4th Floor,Sci Bldg SB 417, New York, NY 10016 USANYU, Grossman Sch Med, Div Rheumatol, New York, NY USA
机构:
Coventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, EnglandCoventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, England
Sandhu, Hardip
Cooper, Samantha
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Coventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, EnglandCoventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, England
Cooper, Samantha
Hussain, Afthab
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Coventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, EnglandCoventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, England
Hussain, Afthab
Mee, Christopher
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Coventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, EnglandCoventry Univ, Fac Hlth & Life Sci, Fac Res Ctr Appl Biol & Exercise Sci, Coventry, W Midlands, England