title: Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Gozde
authors.initials: G
authors.lastname: Dervis Hakim
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Mujde
authors.initials: M
authors.lastname: Soyturk
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Mehtat
authors.initials: M
authors.lastname: Unlu
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Pinar
authors.initials: P
authors.lastname: Ataca
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Meral
authors.initials: M
authors.lastname: Karaman
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Ozgul
authors.initials: O
authors.lastname: Sagol
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Elif
authors.initials: E
authors.lastname: Borekci
authors.affiliation: Gozde Dervis Hakim, Mujde Soyturk, Department of Gastroenterology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir 35340, Turkey.
authors.forename: Osman
authors.initials: O
authors.lastname: Yilmaz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D007213:Indomethacin; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D017208:Rats, Wistar; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D005765:Gastrointestinal Agents; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; C498826:nilotinib; D007213:Indomethacin
keywords: Enterocolitis; Inflammatory bowel disease; Mucosal healing; Platelet-derived growth factor receptor; Rats; Tumor necrosis factor α; Tyrosine kinase inhibitor