Apoptosis, proliferation and inflammation are improved after treatment with the new selective glp-2 receptor agonist, elsiglutide, in a rat model of irinotecan-induced mucositis

Abstract

Introduction: Gastrointestinal mucositis (GIM) is a severe and debilitating side-effect of cancer therapy. There are currently few treatments which effectively prevent or ameliorate GIM. In a previous study it was shown that elsiglutide, a selective glucagon-like peptide-2 (GLP-2) receptor agonist, improved diarrhoea and histological damage associated with irinotecaninduced GIM in a rat model. Increased apoptosis, inflammation and decreased proliferation are associated with irinotecan-induced GIM. It is thought that elsiglutide may improve diarrhoea and damage through altering these gastrointestinal cellular effects. Objectives: To determine if elsiglutide reduces apoptosis and inflammation, and increases proliferation in the small intestinal crypts of the rat, following irinotecan administration. Method: Dark Agouti rats were given irinotecan once (200 mg/kg, 0 hrs) and elsiglutide (0.9 mg/kg or 1.8 mg/kg per day, subcutaneous) for 5 days, and killed at 6, 72 or 120 hrs (n = 6). Markers for apoptosis (Caspase-3), proliferation (Ki67) and inflammation (myeloperoxidase, MPO) were analysed using immunohistochemistry in the jejunum and ileum. Positive stained cells were counted per crypt or field of view (FOV). Results: Apoptosis was significantly (p < 0.05, cells/crypt) reduced following 0.9 mg/kg/day elsiglutide and irinotecan at 6 hrs (Jejunum 10.15 ±1.00; Ileum 13.85 ± 1.44) compared with irinotecan control (Jejunum 14.84 ±1.15; Ileum 22.49 ± 1.08). Proliferation was significantly (p < 0.05, cells/demi-crypt) increased at 72 hrs (peak damage) in this group (Jejunum 31.45 ± 2.78; Ileum 28.47 ± 2.64) compared with irinotecan alone (Jejunum 18.98 ± 2.13; Ileum 18.64 ± 1.62). Staining also showed that 0.9 mg/kg/day elsiglutide given after irinotecan significantly (p < 0.01, cells/FOV) reduces the number of MPO positive inflammatory cells in the jejunum (72 hrs 67.02 ± 6.72; 120 hrs 42.08 ± 5.52) compared with irinotecan alone (72 hrs 106.69 ±6.04; 120 hrs 64.30 ± 7.65). Conclusions: Elsiglutide (0.9 mg/kg/day) decreases apoptosis and inflammation, which may be contributors to irinotecan-induced GIM. In addition, elsiglutide improves proliferation of crypt cells, which may shorten the duration of GIM. These results provide a basis for future studies with elsiglutide to determine the exact mechanisms for this phenomenon.