Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2015; 21(44): 12576-12585
Published online Nov 28, 2015. doi: 10.3748/wjg.v21.i44.12576
Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model
Gozde Dervis Hakim, Mujde Soyturk, Mehtat Unlu, Pinar Ataca, Meral Karaman, Ozgul Sagol, Elif Borekci, Osman Yilmaz
Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey
Mehtat Unlu, Ozgul Sagol, Department of Pathology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey
Pinar Ataca, Elif Borekci, Department of Internal Medicine, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey
Meral Karaman, Osman Yilmaz, Department of Laboratory Animal Science, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey
Author contributions: Dervis Hakim G and Soyturk M designed the research; Dervis Hakim G and Ataca P performed the research; Sagol O and Karaman M contributed new reagents or analytic tools; Borekci E provided technical support; Unlu M And Sagol O contributed to the evaluations of the pathological data; Karaman M and Yilmaz O designed the rat conditions; Soyturk M analyzed the data; Dervis Hakim G wrote the paper; all authors read and approved the final manuscript.
Supported by Dokuz Eylul University Research Committee.
Institutional review board statement: The study was reviewed and approved by the Dokuz Eylul University Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Dokuz Eylul University [protocol number: B.30.2.DEÜ.0.01.00.00/15387].
Conflict-of-interest statement: The authors declare no conflict of interest.
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: Gozde Dervis Hakim, MD, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Mh., Mithatpaşa cad. No. 1606, İnciraltı yerleşkesi, Izmir 35340, Turkey. gozdedervis@gmail.com
Telephone: +90-505-2663138
Received: March 26, 2015
Peer-review started: March 28, 2015
First decision: May 18, 2015
Revised: June 15, 2015
Accepted: September 13, 2015
Article in press: September 14, 2015
Published online: November 28, 2015
Processing time: 246 Days and 11.3 Hours
Abstract

AIM: To investigate the effects of nilotinib in a rat model of indomethacin-induced enterocolitis.

METHODS: Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were divided into the following three groups: control (n = 7), indomethacin (n = 7) and nilotinib (n = 7). A volume of 0.25 mL of physiological serum placebo was administered to the control and indomethacin groups through an orogastric tube for 13 d. To induce enterocolitis, the indomethacin and nilotinib groups received 7.5 mL/kg indomethacin dissolved in 5% sodium bicarbonate and administered subcutaneously in a volume of 0.5 mL twice daily for three days. Nilotinib was administered 20 mg/kg/d in two divided doses to the nilotinib group of rats for 13 d through an orogastric tube, beginning on the same day as indomethacin administration. For 13 d, the rats were fed a standard diet, and their weights were monitored daily. After the rats were sacrificed, the intestinal and colonic tissue samples were examined. The macroscopic and microscopic pathology scores were evaluated. The pathologist stained all tissue samples using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method. Mucosal crypts and apoptotic cells were quantified. The platelet-derived growth factor receptor (PDGFR) α and β scores assessed by immunohistochemical staining method and tissue and serum tumor necrosis factor (TNF) α levels were determined by enzyme-linked immunosorbent assay.

RESULTS: Between days 1 and 13, the rats in the nilotinib and indomethacin groups lost significantly more weight than the controls (-11 g vs +14.14 g, P = 0.013; -30 g vs +14.14 g, P = 0.003). In the small intestinal and colonic tissues, the macroscopic scores were significantly lower in the nilotinib group than in the indomethacin group (1.14 ± 0.38 and 7.29 ± 2.98, P = 0.005; 1.14 ± 0.38 and 7.43 ± 2.64, P = 0.001, respectively), but the values of the nilotinib and indomethacin groups were similar to the control group. In the small intestinal and colonic tissues, the microscopic scores were significantly lower in the nilotinib group than in the indomethacin group (3.43 ± 2.99 and 7.67 ± 3.67, P = 0.043; 2.29 ± 0.76 and 8.80 ± 2.68, P = 0.003, respectively), but the values were similar to the control group. The PDGFR β scores in the small intestine and colon were significantly lower in the nilotinib group than in the indomethacin group (1.43 ± 0.79 and 2.43 ± 0.54, P = 0.021; 1.57 ± 0.54 and 3 ± 0, P =0.001), and the values were similar to controls. The colonic PDGFR α scores were significantly lower in the nilotinib group than in the indomethacin group (1.71 ± 0.49 and 3 ± 0, P = 0.001). The colonic apoptosis scores were significantly lower in the controls than in the nilotinib group (1.57 ± 1.13 and 4 ± 1.29, P = 0.007). Furthermore, the serum and tissue TNF-α levels were similar between the nilotinib and indomethacin groups.

CONCLUSION: In the indomethacin-induced enterocolitis rat model, nilotinib has a positive effect on the macroscopic and microscopic pathologic scores, ensuring considerable mucosal healing. Nilotinib decreases PDGFR α and β levels and increases the colonic apoptotic scores, but it has no significant effects on weight loss and the TNF-α levels.

Keywords: Inflammatory bowel disease; Enterocolitis; Platelet-derived growth factor receptor; Tumor necrosis factor α; Tyrosine kinase inhibitor; Rats; Mucosal healing

Core tip: The etiopathogenesis of inflammatory bowel diseases (IBDs) has not been clearly elucidated. Many management strategies that include targeting particular pathways involved in the development of IBD have been developed. In the present study, we aimed to investigate the effects of nilotinib in a rat model of indomethacin-induced enterocolitis. From our study, it appears that nilotinib had considerable effects on pathological scores, which indicated positive effects in mucosal healing. Nilotinib decreased platelet-derived growth factor receptor α and β and increased the colonic apoptotic scores, but it had no significant effects on weight loss or serum-tissue tumor necrosis factor α levels.