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

Authors :
Nikita Hanning
Michelle De bruyn
Hannah Ceuleers
Tim Boogaerts
Maya Berg
Annemieke Smet
Heiko U. De Schepper
Jurgen Joossens
Alexander L. N. van Nuijs
Joris G. De Man
Koen Augustyns
Ingrid De Meester
Benedicte Y. De Winter
Source :
Pharmaceutics, Vol 13, Iss 6, p 811 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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 H2O) 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.

Details

Language :
English
ISSN :
19994923
Volume :
13
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.bfb9756fc6404ddbabce04e440fd583d
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics13060811