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

• Published in: Frontiers in physiology 2017-06, Vol.8, p.391-391
• Main Authors: McQuade, Rachel M, Stojanovska, Vanesa, Donald, Elizabeth L, Rahman, Ahmed A, Campelj, Dean G, Abalo, Raquel, Rybalka, Emma, Bornstein, Joel C, Nurgali, Kulmira
• Format: Article
• Language: English
• Subjects: chemotherapy; cholinergic neurons; enteric neuropathy; gastrointestinal dysfunction; irinotecan; Physiology
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2017.00391

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 ) 3 times a week for 14 days, sham-treated mice received sterile water (vehicle) injections. 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. 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.