Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models  

作　　者：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 

机构地区：[1]UMR 1331 Toxalim INRA/INPT,Toulouse 31555,France [2]Baruch S.Blumberg Institute,Doylestown,PA 18902,United States [3]Synergy Pharmaceuticals Inc.,420 Lexington Avenue,New York,NY 10170,United States

出　　处：《World Journal of Gastroenterology》2018年第17期1888-1900,共13页世界胃肠病学杂志（英文版）

基　　金：Supported by Synergy Pharmaceuticals Inc.,which provided the funding and the plecanatide,dolcanatide and placebo used for these studies

摘　　要：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 functiAIM 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 functi

关 键 词：Plecanatide Guanylyl cyclase-C AGONISTS Dolcanatide UROGUANYLIN PRECLINICAL cyclic GUANOSINE MONOPHOSPHATE Constipation Inflammatory bowel diseases 

分 类 号：R57[医药卫生—消化系统]