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5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5 H-[1,2]dithiol-3yl)-phenyl Ester (ATB-429), a Hydrogen Sulfide-Releasing Derivative of Mesalamine, Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity
Abstract
H(2)S 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 H(2)S-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-1beta 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 H(2)S 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 H(2)S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.
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“Similarly, mesalamine 3.2 g/day for 12 wk (168) and prednisolone 30 mg/day for 3 wk (52) were not effective in improving the GI symptoms in patients with PI-IBS.”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [52]
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Metadata
- Authors
- Distrutti, E., Sediari, L., Mencarelli, A., Renga, B., Orlandi, S., Russo, G., Caliendo, G., Santagada, V., Cirino, G., Wallace, J. L., & Fiorucci, S.
- Affiliations
- University of Perugia (IT)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 319
- Issue
- 1
- Pages
- 447-458
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2166470604
- Cited by
- 144
- References
- 41
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 2 · 2022: 9 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 12 · 2014: 13 · 2013: 14 · 2012: 6
- FWCI
- 9.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- hydrogen sulfide, 5-aminosalicylic acid, irritable bowel syndrome, colorectal distension, antinociception, ATP-sensitive potassium channels, glibenclamide, Fos expression, cyclooxygenase-2, IL-1β, colitis, allodynia, visceral pain, neuromodulation
- MeSH terms
- Analgesics, Animals, Colon, Disulfides, Hydrogen Sulfide, Male, Spinal Cord, Rats, Wistar, Mesalamine, Potassium Channel Blockers, Irritable Bowel Syndrome, Rats
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