Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2018; 24(17): 1888-1900
Published online May 7, 2018. doi: 10.3748/wjg.v24.i17.1888
Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models
Illona-Marie Boulete, Anusha Thadi, Catherine Beaufrand, Viren Patwa, Apoorva Joshi, John A Foss, E Priya Eddy, Helene Eutamene, Vaseem A Palejwala, Vassilia Theodorou, Kunwar Shailubhai
Illona-Marie Boulete, Catherine Beaufrand, Helene Eutamene, Vassilia Theodorou, UMR 1331 Toxalim INRA/INPT, Toulouse 31555, France
Anusha Thadi, Viren Patwa, Apoorva Joshi, Kunwar Shailubhai, Baruch S. Blumberg Institute, Doylestown, PA 18902, United States
John A Foss, E Priya Eddy, Vaseem A Palejwala, Kunwar Shailubhai, Synergy Pharmaceuticals Inc., 420 Lexington Avenue, New York, NY 10170, United States
Author contributions: Boulete IM and Thadi A contributed to this work equally; Thadi A, Patwa V, Joshi A, Palejwala VA and Shailubhai K contributed to the conception or design of the work; Boulete IM, Thadi A, Beaufrand C, Patwa V, Joshi A, Foss JA, Eddy EP, Eutamene H, Palejwala VA, Theodorou V and Shailubhai K contributed to the acquisition, analysis or interpretation of data for the work; all authors participated in drafting and critically revising the work for important intellectual content, approved the final version of the manuscript for submission, agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved and qualify for authorship.
Supported by Synergy Pharmaceuticals Inc., which provided the funding and the plecanatide, dolcanatide and placebo used for these studies.
Institutional animal care and use committee statement: Animal care and handling procedures for ex vivo studies performed in the United States were as per the approved protocol by the Institutional Animal Care and Use Committee of Lampire Biologicals (Pipersville, PA, United States). Animal handling procedures for in vivo studies conducted in France were approved by the Institutional Animal Care and Use Local Committee (Toulouse, France).
Conflict-of-interest statement: Foss JA, Eddy EP, Palejwala VA and Shailubhai K are employees and/or stockholders of Synergy Pharmaceuticals Inc. All other authors have no conflicts to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Kunwar Shailubhai, PhD, Professor, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, United States. shailubhai@gmail.com
Telephone: +1-215-5896308
Received: January 25, 2018
Peer-review started: January 26, 2018
First decision: February 5, 2018
Revised: February 23, 2018
Accepted: March 18, 2018
Article in press: March 18, 2018
Published online: May 7, 2018
Processing time: 100 Days and 19.3 Hours
Abstract
AIM

To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeability, integrity of tight junctions and on suppression of visceral hypersensitivity.

METHODS

Transport of fluorescein isothiocyanate (FITC)-dextran was measured to assess permeability across cell monolayers and rat colon tissues. Effects of plecanatide and dolcanatide on the integrity of tight junctions in Caco-2 and T84 monolayers and on the expression and localization of occludin and zonula occludens-1 (ZO-1) were examined by immunofluorescence microscopy. Anti-nociceptive activity of these agonists was evaluated in trinitrobenzene sulfonic acid (TNBS)-induced inflammatory as well as in non-inflammatory partial restraint stress (PRS) rat models. Statistical significance between the treatment groups in the permeability studies were evaluated using unpaired t-tests.

RESULTS

Treatment of T84 and Caco-2 monolayers with lipopolysaccharide (LPS) rapidly increased permeability, which was effectively suppressed when monolayers were also treated with plecanatide or dolcanatide. Similarly, when T84 and Caco-2 monolayers were treated with LPS, cell surface localization of tight junction proteins occludin and ZO-1 was severely disrupted. When cell monolayers were treated with LPS in the presence of plecanatide or dolcanatide, occludin and ZO-1 were localized at the cell surface of adjoining cells, similar to that observed for vehicle treated cells. Treatment of cell monolayers with plecanatide or dolcanatide without LPS did not alter permeability, integrity of tight junctions and cell surface localization of either of the tight junction proteins. In rat visceral hypersensitivity models, both agonists suppressed the TNBS-induced increase in abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity, and both agonists also reduced colonic hypersensitivity in the PRS model.

CONCLUSION

Our results suggest that activation of GC-C signaling might be involved in maintenance of barrier function, possibly through regulating normal localization of tight junction proteins. Consistent with these findings, plecanatide and dolcanatide showed potent anti-nociceptive activity in rat visceral hypersensitivity models. These results imply that activation of GC-C signaling may be an attractive therapeutic approach to treat functional constipation disorders and inflammatory gastrointestinal conditions.

Keywords: Plecanatide, Guanylyl cyclase-C agonists, Dolcanatide, Uroguanylin, Preclinical, Cyclic guanosine monophosphate, Constipation, Inflammatory bowel diseases

Core tip: Our results indicate that plecanatide and dolcanatide, guanylate cyclase-C receptor agonists designed to replicate the activity of the human intestinal peptide uroguanylin, maintain intestinal barrier function and exhibit potent anti-nociceptive activity in animal models of visceral hypersensitivity, suggesting a novel mechanism, beyond the well described secretory function, for these agonists in the treatment of functional constipation disorders and inflammatory bowel disease.