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      Therapeutic effect of protease-activated receptor 2 agonist SLIGRL-NH 2 on loperamide-induced Sprague-Dawley rat constipation model and the related mechanism

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          Abstract

          Purpose

          To investigate the therapeutic effects of protease-activated receptor 2 (PAR-2) agonist SLIGRL-NH 2 on loperamide-induced Sprague-Dawley (SD) rat constipation animal models.

          Materials and methods

          Loperamide was injected subcutaneously to induce constipation twice a day for 3 days. SD rats (n = 30) were randomly divided into five groups: non-constipation group (control, n = 6), constipation group (constipation, n = 6), constipation + SLIGRL-NH 2 low-dosage group (SLIGRL-NH 2 low, n=6), constipation + SLIGRL-NH 2 high-dosage group (SLIGRL-NH 2 high, n = 6), and constipation + prucalopride (positive control, n = 6). The SLIGRL-NH 2 low group and SLIGRL-NH 2 high group were administered with 2.5 μmol/kg and 5 μmol/kg SLIGRL-NH 2, respectively, and the prucalopride group received 2 mg/kg prucalopride. The control and constipation group received 1× PBS under the same pattern. SLIGRL-NH 2 and prucalopride were orally administrated once daily for 7 days. On the final day of oral administration, food intake, water intake, the number of stool pellets, weight, and fecal water content was calculated; moreover, the colons of rats in different groups were collected and histological features were examined by hematoxylin and eosin staining; furthermore, the expression of anoctamin-1 was determined by Immunohistochemical methods, and the expressions of c-kit and PAR-2 were examined using real-time quantitative polymerase chain reaction and Western blot methods; finally, the expressions of neurotransmitter vasoactive intestinal peptide (VIP) and substance P (SP) were examined using enzyme-linked immuno-sorbent assay methods.

          Results

          The feeding and excretion behaviors, intestinal transit ratio, and the histological feature of the colon in the constipated rats were all improved by SLIGRL-NH 2 treatment; moreover, SLIGRL-NH 2 treatment induced significant increase in the expression of PAR-2 and also increased number of interstitial Cajal cells. Furthermore, SLIGRL-NH 2 also decreased the contents of the inhibitory neurotransmitter VIP and increased the expression of the excitatory neurotransmitter SP. High dose of SLIGRL-NH 2 has shown similar anti-constipation effects as prucalopride.

          Conclusion

          These results suggested that SLIGRL-NH 2 can enhance gastrointestinal transit and alleviate in rats with loperamide-induced constipation.

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          Most cited references 31

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          Chronic constipation: a survey of the patient perspective.

          Constipation is a common, often chronic, gastrointestinal motility disorder characterized by such symptoms as straining, hard stool, and infrequent defecation. Published literature is limited regarding symptom prevalence, healthcare-seeking behaviour, and patient satisfaction with traditional therapies for chronic constipation. To assess the prevalence of chronic constipation among a random sample of Americans, to identify the frequency, severity and bothersomeness of their symptoms, and to assess satisfaction levels with traditional treatments. All members (N = 37,004) of the Knowledge Networks Panel, representative of the US population, participated in a web-based survey. Eligibility was established using a six-question screener. Of the 24,090 panellists consenting to participate, 557 met eligibility requirements and took the 45-question survey. The most prevalent symptom was straining (79%). Hard stool and straining were the top two severe symptoms, and bloating, straining and hard stool were the top three bothersome symptoms. Symptoms affected quality of life of more than half (52%) the respondents. Among those who worked or went to school, 12% experienced reduced productivity and a mean of 2.4 days of absence in the month before the survey. Most respondents had used (96%) or were using (72%) constipation relief therapy; however, nearly half (47%) were not completely satisfied, mainly because of efficacy (82%) and safety (16%) concerns. Chronic constipation is common. Individual symptoms are often severe and bothersome, and many patients are dissatisfied with traditional treatment options, primarily because of lack of efficacy.
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            Systematic review on the management of chronic constipation in North America.

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              Decreased interstitial cell of cajal volume in patients with slow-transit constipation.

              The cause of slow-transit constipation is incompletely understood. Recent observations suggest a central role for interstitial cells of Cajal in the control of intestinal motility. The aim of this study was to determine the volume of interstitial cells of Cajal in the normal sigmoid colon and in the sigmoid colon from patients with slow transit constipation. Sigmoid colonic samples were stained with antibodies to protein gene product 9.5, c-Kit, and alpha-smooth muscle actin. Three-dimensional reconstruction of regions of interest was performed using consecutive images collected on a laser scanning confocal microscope and ANALYZE software. Volume of interstitial cells of Cajal was significantly decreased in all layers of sigmoid colonic specimens from patients with slow-transit constipation compared with normal controls. Neuronal structures within the colonic circular smooth muscle layer were also decreased. A decrease in the volume of interstitial cells of Cajal may play an important role in the pathophysiology of slow-transit constipation.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                01 August 2018
                : 12
                : 2403-2411
                Affiliations
                [1 ]Department of Colorectal Surgery, The First People’s Hospital of Lianyungang, Lianyungang 222002, China
                [2 ]Department of Neurosurgery, The First People’s Hospital of Lianyungang, Lianyungang 222002, China
                [3 ]Department of Gastroenterology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
                [4 ]Department of Gastroenterology, Lianyungang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Lianyungang 222000, China, dr_yintingwei@ 123456outlook.com
                Author notes
                Correspondence: Yinting Wei, Department of Gastroenterology, Lianyungang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, 160 Chaoyang Middle Road, Lianyungang 222000, China, Tel/fax +86 518 8557 4088, Email dr_yintingwei@ 123456outlook.com
                Article
                dddt-12-2403
                10.2147/DDDT.S160628
                6078190
                © 2018 Zhang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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