Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats.

Autor: Hanning N; Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium.; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium., De Bruyn M; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium.; Laboratory of Medical Biochemistry, University of Antwerp, 2610 Wilrijk, Belgium., Ceuleers H; Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium.; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium., Boogaerts T; Toxicological Centre, University of Antwerp, 2610 Wilrijk, Belgium., Berg M; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium., Smet A; Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium.; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium., De Schepper HU; Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium.; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium., Joossens J; Laboratory of Medicinal Chemistry, University of Antwerp, 2610 Wilrijk, Belgium., van Nuijs ALN; Toxicological Centre, University of Antwerp, 2610 Wilrijk, Belgium., De Man JG; Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium.; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium., Augustyns K; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium.; Laboratory of Medicinal Chemistry, University of Antwerp, 2610 Wilrijk, Belgium., De Meester I; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium.; Laboratory of Medical Biochemistry, University of Antwerp, 2610 Wilrijk, Belgium., De Winter BY; Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium.; Infla-Med, Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium.
Jazyk: angličtina
Zdroj: Pharmaceutics [Pharmaceutics] 2021 May 29; Vol. 13 (6). Date of Electronic Publication: 2021 May 29.
DOI: 10.3390/pharmaceutics13060811
Abstrakt: Dysregulation of the protease-antiprotease balance in the gastrointestinal tract has been suggested as a mechanism underlying visceral hypersensitivity in conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). We aimed to study the potential therapeutic role of an intracolonically administered serine protease inhibitor for the treatment of abdominal pain in a post-inflammatory rat model for IBS. An enema containing 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male Sprague-Dawley rats, whereas controls received a saline solution. Colonoscopies were performed to confirm colitis and follow-up mucosal healing. In the post-inflammatory phase, the serine protease inhibitor UAMC-00050 (0.1-5 mg/kg) or its vehicle alone (5% DMSO in H 2 O) was administered in the colon. Thirty minutes later, visceral mechanosensitivity to colorectal distensions was quantified by visceromotor responses (VMRs) and local effects on colonic compliance and inflammatory parameters were assessed. Specific proteolytic activities in fecal and colonic samples were measured using fluorogenic substrates. Pharmacokinetic parameters were evaluated using bioanalytical measurements with liquid chromatography-tandem mass spectrometry. Post-inflammatory rats had increased trypsin-like activity in colonic tissue and elevated elastase-like activity in fecal samples compared to controls. Treatment with UAMC-00050 decreased trypsin-like activity in colonic tissue of post-colitis animals. Pharmacokinetic experiments revealed that UAMC-00050 acted locally, being taken up in the bloodstream only minimally after administration. Local administration of UAMC-00050 normalized visceral hypersensitivity. These results support the role of serine proteases in the pathophysiology of visceral pain and the potential of locally administered serine protease inhibitors as clinically relevant therapeutics for the treatment of IBS patients with abdominal pain.
Databáze: MEDLINE
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