Irinotecan-Induced Gastrointestinal Dysfunction Is Associated with Enteric Neuropathy, but Increased Numbers of Cholinergic Myenteric Neurons

Abstract

Gastrointestinal dysfunction is a common side-effect of chemotherapy leading to dose reductions and treatment delays. These side-effects may persist up to 10 years post-treatment. A topoisomerase I inhibitor, irinotecan (IRI), commonly used for the treatment of colorectal cancer, is associated with severe acute and delayed-onset diarrhea. The long-term effects of IRI may be due to damage to enteric neurons innervating the gastrointestinal tract and controlling its functions. Balb/c mice received intraperitoneal injections of IRI (30 mg/kg−1) 3 times a week for 14 days, sham-treated mice received sterile water (vehicle) injections. In vivo analysis of gastrointestinal transit via serial x-ray imaging, facal water content, assessment of gross morphological damage and immunohistochemical analysis of myenteric neurons were performed at 3, 7 and 14 days following the first injection and at 7 days post-treatment. Ex vivo colonic motility was analyzed at 14 days following the first injection and 7 days post-treatment. Mucosal damage and inflammation were found following both short and long-term treatment with IRI. IRI-induced neuronal loss and increases in the number and proportion of ChAT-IR neurons and the density of VAChT-IR fibers were associated with changes in colonic motility, gastrointestinal transit and fecal water content. These changes persisted in post-treatment mice. Taken together this work has demonstrated for the first time that IRI-induced inflammation, neuronal loss and altered cholinergic expression is associated with the development of IRI-induced long-term gastrointestinal dysfunction and diarrhea.

Protective effect of magnolol on oxaliplatin‐induced intestinal injury in mice

“…These selected sections of colon were analyzed and scored the following parameters: changes in crypt architecture (0–5), reduction in crypt length (0–5), mucosal ulceration (0–5), and immune cell infiltration (0–5; total score 20). (McQuade et al, ) The morphological assessment was performed under a light microscope at a magnification of 100, which was connected to a computer with an image analysis program (Nikon NIS‐Elements).…”

“…Fecal parameters were analyzed according to earlier studies (McQuade et al, ; Zhou et al, ). Briefly, individual mice were placed in clean cages and allowed ad libitum access to food and water for 15–40 min.…”

“…Pellets were then dehydrated for 72 hr at 37°C prior to measurement of the dry weight. Water content was calculated as the difference between the fresh pellets weight and dry weight (McQuade et al, ; Rahman, Robinson, Brookes, Eri, & Nurgali, ). Mice feces were collected at the sixth day.…”

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

“…It should also be noted that the delay in the gastric emptying was clearly observed as an increase in MAT value in the irinotecan-treated rats in the APAP study, but not in the DAB study. McQuade et al (2017) have previously reported that the gastric emptying rate was decreased by irinotecan treatment. Taken together, these findings suggest that the decrease in the plasma concentration of DAB is primarily explained by the increased P-gp function but not by the decrease in passive diffusion or gastric emptying.…”

Fluoroscopic Characterization of Colonic Dysmotility Associated to Opioid and Cannabinoid Agonists in Conscious Rats

“…For example, fecal pellets from mice repeatedly treated with the antineoplastic drug irinotecan showed statistically significant differences in length along treatment. 45 Likewise, vincristine, another antitumoral drug, reduced the diameter of fecal pellets in the rat, when repeatedly administered. 16 Whatever the case may be, the fact that morphometric values of the endogenous fecal pellets were not significantly changed in our experimental conditions imply that changes in fecal pellet propulsion did not involve altered mechanical stimulation of the colon associated to changes in fecal pellet size.…”