Document Detail


Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats.
MedLine Citation:
PMID:  19333545     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: 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.
METHODS: Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration.
RESULTS: 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 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected.
CONCLUSION: 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.
Authors:
Shigeto Koizumi; Masaru Odashima; Michiro Otaka; Mario Jin; Joel Linden; Sumio Watanabe; Hirohide Ohnishi
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Publication Detail:
Type:  Journal Article     Date:  2009-04-01
Journal Detail:
Title:  Journal of gastroenterology     Volume:  44     ISSN:  0944-1174     ISO Abbreviation:  J. Gastroenterol.     Publication Date:  2009  
Date Detail:
Created Date:  2009-05-12     Completed Date:  2009-07-21     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  9430794     Medline TA:  J Gastroenterol     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  419-25     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine A2 Receptor Agonists
Adenosine A2 Receptor Antagonists
Animals
Anti-Inflammatory Agents, Non-Steroidal / toxicity*
Chemokine CXCL1 / metabolism
Dinoprostone / metabolism
Gastric Mucosa / drug effects*,  metabolism,  pathology
Indomethacin / toxicity*
Inflammation
Interleukin-1beta / metabolism
Male
Peroxidase / metabolism
Piperidines / pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Adenosine A2A / metabolism*
Stomach Ulcer / chemically induced,  metabolism,  pathology
Triazines / pharmacology
Triazoles / pharmacology
Tumor Necrosis Factor-alpha / metabolism
Grant Support
ID/Acronym/Agency:
R01 HL037942/HL/NHLBI NIH HHS; R01 HL037942-21/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/ATL 313; 0/Adenosine A2 Receptor Agonists; 0/Adenosine A2 Receptor Antagonists; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Chemokine CXCL1; 0/Cxcl1 protein, rat; 0/Interleukin-1beta; 0/Piperidines; 0/Receptor, Adenosine A2A; 0/Triazines; 0/Triazoles; 0/Tumor Necrosis Factor-alpha; 0/ZM 241385; EC 1.11.1.7/Peroxidase; K7Q1JQR04M/Dinoprostone; XXE1CET956/Indomethacin
Comments/Corrections

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