Activation of the bile acid receptor GPBAR1 protects against gastrointestinal injury caused by non‐steroidal anti‐inflammatory drugs and aspirin in mice. (18th December 2012)

• Record Type: Journal Article
• Authors: Cipriani, Sabrina; Mencarelli, Andrea; Bruno, Angela; Renga, Barbara; Distrutti, Eleonora; Santucci, Luca; Baldelli, Franco; Fiorucci, Stefano
• Is Part Of: British journal of pharmacology. Volume 168:Number 1(2013:Jan.)
• Page Start: 225
• Page End: 237
• Publication Date: 2012-12-18
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/j.1476-5381.2012.02128.x
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph2128-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Low doses of aspirin (acetylsalicylic acid; ASA) and non‐steroidal anti‐inflammatory drugs (NSAIDs) increase the risk of gastrointestinal bleeding. GPBAR1 is a bile acid receptor expressed in the gastrointestinal tract. Here, we have investigated whether GPBAR1 was required for mucosal protection in models of gastrointestinal injury caused by ASA and NSAIDs.</p> </sec> <sec id="bph2128-sec-0002" sec-type="section"> <title>Experimental Approch</title> <p>GPBAR1<sup>+/+</sup> and GPBAR1<sup>−/−</sup> mice were given ASA (10–50 mg.kg<sup>−1</sup>) or naproxen. Gastric and intestinal mucosal damage was assessed by measuring lesion scores.</p> </sec> <sec id="bph2128-sec-0003" sec-type="section"> <title>Key Results</title> <p>Expression of GPBAR1, mRNA and protein, was detected in mouse stomach. Mice lacking GPBAR1 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<sub>2</sub>S and NO, in the stomach. Treating GPBAR1<sup>+/+</sup> mice with two GPBAR1 agonists, ciprofloxacin and betulinic acid, rescued mice from gastric injury caused by ASA and NSAIDs. The protective effect of these agents was lost in GPBAR1<sup>−/−</sup> mice. Inhibition of CSE by DL‐propargylglycine completely reversed protection afforded by ciprofloxacin in wild type mice, whereas treating mice with an H<sub>2</sub>S donor restored the protective effects of ciprofloxacin in GPBAR1<sup>−/−</sup> mice. Deletion of GPBAR1 altered the morphology of the small intestine and increased sensitivity to injury caused by naproxen.</p> </sec> <sec id="bph2128-sec-0004" sec-type="section"> <title>Conclusion and Implications</title> <p>GPBAR1 is essential to maintain gastric and intestinal mucosal integrity. GPBAR1 agonists protect against gastrointestinal injury caused by ASA and NSAIDs by a COX‐independent mechanism.</p> </sec> </abstract>