Amitriptyline prevents CPT-11-induced early-onset diarrhea and colonic apoptosis without reducing overall gastrointestinal damage in a rat model of mucositis.

Abstract

Gastrointestinal mucositis (GIM) is one of the most debilitating side effects of the chemotherapy agent, irinotecan hydrochloride (CPT-11). The toll-like receptor (TLR) pathway is a key mediator implicated in the pathophysiology underlying GIM. The tricyclic antidepressant amitriptyline has been shown to inhibit TLR2 and TLR4 activity in in vitro models. The aim of this study was therefore to investigate the effect of amitriptyline on the development of GIM following CPT-11. Male albino Wistar rats were treated with either CPT-11 (125mg/kg, i.p., n = 18), amitriptyline (20mg/kg, n = 18), both agents (n = 18), or vehicle control (n = 18) and killed at 6, 48, or 96h. Differences between groups in measurements of gastrointestinal toxicity (diarrhea and weight loss), mucosal injury (apoptosis and histopathology score), colonic expression of TLRs, and pro-inflammatory cytokines were determined. CPT-11-induced diarrhea and colonic apoptosis were inhibited by amitriptyline at 6h. However, rats were not protected from weight loss or mucosal injury over the time course of CPT-11-induced GIM. Interleukin-1 beta transcript expression was significantly decreased with amitriptyline treatment at 6h, although protein expression did not differ between groups. There was no change in TLR4 or TLR2 expression in any group. Prophylactic amitriptyline was able to inhibit early intestinal damage in this rat model of CPT-11-induced GIM, but exacerbated late-onset injury. These findings do not support use of amitriptyline as an approach for mitigation of GIM in this setting.