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Activation of the bile acid receptor GPBAR 1 protects against gastrointestinal injury caused by non‐steroidal anti‐inflammatory drugs and aspirin in mice
Author(s) -
Cipriani Sabrina,
Mencarelli Andrea,
Bruno Angela,
Renga Barbara,
Distrutti Eleonora,
Santucci Luca,
Baldelli Franco,
Fiorucci Stefano
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02128.x
Subject(s) - pharmacology , aspirin , naproxen , stomach , gastrointestinal tract , medicine , acetaminophen , inflammation , small intestine , hmgb1 , bile acid , chemistry , pathology , alternative medicine
Background and Purpose Low doses of aspirin (acetylsalicylic acid; ASA ) and non‐steroidal anti‐inflammatory drugs ( NSAIDs ) increase the risk of gastrointestinal bleeding. GPBAR 1 is a bile acid receptor expressed in the gastrointestinal tract. Here, we have investigated whether GPBAR 1 was required for mucosal protection in models of gastrointestinal injury caused by ASA and NSAIDs . Experimental Approch GPBAR 1 +/+ and GPBAR 1 −/− mice were given ASA (10–50 mg.kg −1 ) or naproxen. Gastric and intestinal mucosal damage was assessed by measuring lesion scores. Key Results Expression of GPBAR 1, m RNA and protein, was detected in mouse stomach. Mice lacking GPBAR 1 were more sensitive to gastric and intestinal injury caused by ASA and NSAIDs and exhibited a markedly reduced expression of cystathionine‐γ‐liase ( CSE ), cystathionine‐β‐synthase ( CBS ) and endothelial NOS enzymes required for generation of H 2 S and NO , in the stomach. Treating GPBAR 1 +/+ mice with two GPBAR 1 agonists, ciprofloxacin and betulinic acid, rescued mice from gastric injury caused by ASA and NSAIDs . The protective effect of these agents was lost in GPBAR 1 −/− mice. Inhibition of CSE by DL ‐propargylglycine completely reversed protection afforded by ciprofloxacin in wild type mice, whereas treating mice with an H 2 S donor restored the protective effects of ciprofloxacin in GPBAR 1 −/− mice. Deletion of GPBAR 1 altered the morphology of the small intestine and increased sensitivity to injury caused by naproxen. Conclusion and Implications GPBAR 1 is essential to maintain gastric and intestinal mucosal integrity. GPBAR 1 agonists protect against gastrointestinal injury caused by ASA and NSAIDs by a COX ‐independent mechanism.