Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats

被引:18
|
作者
Koizumi, Shigeto [1 ]
Odashima, Masaru [1 ]
Otaka, Michiro [2 ]
Jin, Mario [1 ]
Linden, Joel [3 ]
Watanabe, Sumio [2 ]
Ohnishi, Hirohide [1 ]
机构
[1] Akita Univ, Sch Med, Dept Gastroenterol, Akita 0108543, Japan
[2] Juntendo Univ, Dept Gastroenterol, Tokyo, Japan
[3] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA USA
关键词
NSAIDs; Gastric ulcer; Adenosine A(2A) receptor; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NECROSIS-FACTOR-ALPHA; REPERFUSION INJURY; SUPEROXIDE GENERATION; LIPID-PEROXIDATION; WATER-IMMERSION; A(2B) RECEPTORS; INHIBITS IL-12; MECHANISMS; PATHOGENESIS;
D O I
10.1007/s00535-009-0028-8
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:419 / 425
页数:7
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