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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5H-[1,2]dithiol-3yl)-phenyl Ester (ATB-429), a Hydrogen Sulfide-Releasing Derivative of Mesalamine, Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity

Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Perugia, Italy (E.D., L.S., A.M., B.R., S.O., G.R., S.F.); Dipartimento di Chimica Farmaceutica e Tossicologia e Dipartimento di Farmacologia Sperimentale, University of Naples, Naples, Italy (G.Ca., V.S., G.Ci.); and Inflammation Research Network, Department of Pharmacology, University of Calgary, Calgary, Alberta, Canada (J.L.W.)

H₂S functions as a neuromodulator and exerts anti-inflammatory activities. Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract. In this study, we have investigated the role of a novel H₂S-releasing derivative of mesalamine (5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats. Four graded (0.4-1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response and spinal c-Fos expression. In healthy rats, ATB-429 dose dependently (25, 50, or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRD-induced overexpression of spinal c-FOS mRNA, whereas mesalamine had no effect. ATB-429-induced antinociception was reversed by glibenclamide, a ATP-sensitive K⁺ (K_ATP) channel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of postinflammatory hypersensitivity (4 weeks after colitis induction). At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in postcolitic rats. Colonic cyclooxygenase-2 and interkeukin-1 mRNA and spinal c-FOS mRNA expression were significantly down-regulated by ATB-429, but not by mesalamine. ATB-429, but not mesalamine, increased blood concentrations of H₂S in both healthy and postcolitic rats. Taken together, these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K_ATP channel-mediated mechanism. This study provides evidence that H₂S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.

Address correspondence to: Dr. Eleonora Distrutti, Clinica di Gastroenterologia, Policlinico Monteluce, University of Perugia, Via Enrico Dal Pozzo, 06122 Perugia, Italy. E-mail: eleonoradistrutti{at}katamail.com