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
ARTICLE HIGHLIGHTS
Research background

Activation of guanylate cyclase-C (GC-C) signaling is an emerging therapeutic target for the treatment of gastrointestinal disorders and inflammatory diseases. Loss of GC-C signaling may disrupt intestinal water and ion secretion, resulting in chronic idiopathic constipation or irritable bowel syndrome with constipation (IBS-C). In addition, reduced GC-C signaling may also disrupt intestinal barrier function due to increased paracellular permeability, allowing entry of inflammatory mediators to promote low-grade inflammation and visceral hypersensitivity associated with abdominal pain in IBS-C patients.

Research motivation

Plecanatide and dolcanatide are analogs of human uroguanylin, the endogenous agonist of GC-C receptors, and are targeted at the treatment of functional constipation disorders and inflammatory bowel disease (IBD), respectively; therefore we sought to further characterize the mechanisms of these peptides using in vitro and in vivo models of these diseases.

Research objectives

To discern the role of plecanatide and dolcanatide in the maintenance of mucosal membrane integrity and in the reduction of visceral hypersensitivity in inflammatory and non-inflammatory animal models.

Research methods

Maintenance of epithelial cell integrity by plecanatide or dolcanatide in response to chemical challenge by lipopolysaccharide (LPS) was assessed using cell lines, as well as tissue harvested from rat intestines. Paracellular permeability was determined by calculating the flux of fluorescein isothiocyanate (FITC)-dextran using immunofluorescence microscopy. Electromyographic recordings were used to assess suppression of visceral hypersensitivity by plecanatide or dolcanatide in rat models of inflammatory and non-inflammatory visceral pain.

Research results

Plecanatide or dolcanatide effectively suppressed LPS-induced paracellular permeability. Oral treatment with plecanatide or dolcanatide considerably attenuated visceral hypersensitivity in inflammatory and non-inflammatory models of visceral pain.

Research conclusions

The data presented suggest further mechanisms, in addition to their better known secretory effects, whereby plecanatide or dolcanatide treatment, through activation of the GC-C receptor, may protect the epithelial barrier from increased paracellular permeability and provide anti-nociceptive activity, which may ultimately benefit patients with functional constipation disorders and IBD.

Research perspectives

Plecanatide is a secretagogue approved in the US for the treatment of adults with chronic idiopathic constipation or IBS-C. Dolcanatide is under evaluation for the treatment of opioid-induced constipation and ulcerative colitis. This study provides preclinical evidence that plecanatide and dolcanatide may act to preserve the integrity of the intestinal epithelium and to provide anti-nociceptive activity, supporting ongoing investigations of these peptides in functional constipation disorders and IBD.