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Therapeutic effect of protease-activated receptor 2 agonist SLIGRL-NH2 on loperamide-induced Sprague-Dawley rat constipation model and the related mechanism.
Drug Des Devel Ther. 2018; 12:2403-2411.DD

Abstract

PURPOSE

To investigate the therapeutic effects of protease-activated receptor 2 (PAR-2) agonist SLIGRL-NH2 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-NH2 low-dosage group (SLIGRL-NH2 low, n=6), constipation + SLIGRL-NH2 high-dosage group (SLIGRL-NH2 high, n = 6), and constipation + prucalopride (positive control, n = 6). The SLIGRL-NH2 low group and SLIGRL-NH2 high group were administered with 2.5 μmol/kg and 5 μmol/kg SLIGRL-NH2, respectively, and the prucalopride group received 2 mg/kg prucalopride. The control and constipation group received 1× PBS under the same pattern. SLIGRL-NH2 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-NH2 treatment; moreover, SLIGRL-NH2 treatment induced significant increase in the expression of PAR-2 and also increased number of interstitial Cajal cells. Furthermore, SLIGRL-NH2 also decreased the contents of the inhibitory neurotransmitter VIP and increased the expression of the excitatory neurotransmitter SP. High dose of SLIGRL-NH2 has shown similar anti-constipation effects as prucalopride.

CONCLUSION

These results suggested that SLIGRL-NH2 can enhance gastrointestinal transit and alleviate in rats with loperamide-induced constipation.

Authors+Show Affiliations

Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China.Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China.Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China.Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China.Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China.Department of Neurosurgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China.Department of Gastroenterology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.Department of Gastroenterology, Lianyungang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Lianyungang 222000, China, dr_yintingwei@outlook.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30122898

Citation

Zhang, Yonggang, et al. "Therapeutic Effect of Protease-activated Receptor 2 Agonist SLIGRL-NH2 On Loperamide-induced Sprague-Dawley Rat Constipation Model and the Related Mechanism." Drug Design, Development and Therapy, vol. 12, 2018, pp. 2403-2411.
Zhang Y, Ge T, Xiang P, et al. Therapeutic effect of protease-activated receptor 2 agonist SLIGRL-NH2 on loperamide-induced Sprague-Dawley rat constipation model and the related mechanism. Drug Des Devel Ther. 2018;12:2403-2411.
Zhang, Y., Ge, T., Xiang, P., Mao, H., Tang, S., Li, A., Lin, L., & Wei, Y. (2018). Therapeutic effect of protease-activated receptor 2 agonist SLIGRL-NH2 on loperamide-induced Sprague-Dawley rat constipation model and the related mechanism. Drug Design, Development and Therapy, 12, 2403-2411. https://doi.org/10.2147/DDDT.S160628
Zhang Y, et al. Therapeutic Effect of Protease-activated Receptor 2 Agonist SLIGRL-NH2 On Loperamide-induced Sprague-Dawley Rat Constipation Model and the Related Mechanism. Drug Des Devel Ther. 2018;12:2403-2411. PubMed PMID: 30122898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic effect of protease-activated receptor 2 agonist SLIGRL-NH2 on loperamide-induced Sprague-Dawley rat constipation model and the related mechanism. AU - Zhang,Yonggang, AU - Ge,Tingrui, AU - Xiang,Ping, AU - Mao,Haibing, AU - Tang,Shumin, AU - Li,Aimin, AU - Lin,Lin, AU - Wei,Yinting, Y1 - 2018/08/01/ PY - 2018/8/21/entrez PY - 2018/8/21/pubmed PY - 2018/11/28/medline KW - PAR-2 KW - SLIGRL-NH2 KW - constipation KW - interstitial Cajal cells KW - loperamide SP - 2403 EP - 2411 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 12 N2 - PURPOSE: To investigate the therapeutic effects of protease-activated receptor 2 (PAR-2) agonist SLIGRL-NH2 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-NH2 low-dosage group (SLIGRL-NH2 low, n=6), constipation + SLIGRL-NH2 high-dosage group (SLIGRL-NH2 high, n = 6), and constipation + prucalopride (positive control, n = 6). The SLIGRL-NH2 low group and SLIGRL-NH2 high group were administered with 2.5 μmol/kg and 5 μmol/kg SLIGRL-NH2, respectively, and the prucalopride group received 2 mg/kg prucalopride. The control and constipation group received 1× PBS under the same pattern. SLIGRL-NH2 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-NH2 treatment; moreover, SLIGRL-NH2 treatment induced significant increase in the expression of PAR-2 and also increased number of interstitial Cajal cells. Furthermore, SLIGRL-NH2 also decreased the contents of the inhibitory neurotransmitter VIP and increased the expression of the excitatory neurotransmitter SP. High dose of SLIGRL-NH2 has shown similar anti-constipation effects as prucalopride. CONCLUSION: These results suggested that SLIGRL-NH2 can enhance gastrointestinal transit and alleviate in rats with loperamide-induced constipation. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/30122898/Therapeutic_effect_of_protease_activated_receptor_2_agonist_SLIGRL_NH2_on_loperamide_induced_Sprague_Dawley_rat_constipation_model_and_the_related_mechanism_ DB - PRIME DP - Unbound Medicine ER -