GLP-2 Prevents Neuronal and Glial Changes in the Distal Colon of Mice Chronically Treated with Cisplatin.

Patrizia Nardini,Alessandro Pini,Maria Giuliana Vannucchi,Anne Bessard,Michel Neunlist,Emilie Duchalais,Elena Niccolai

doi:10.3390/ijms21228875

Abstract

Cisplatin is a chemotherapeutic agent widely used for the treatment of solid cancers. Its administration is commonly associated with acute and chronic gastrointestinal dysfunctions, likely related to mucosal and enteric nervous system (ENS) injuries, respectively. Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone exerting trophic/reparative activities on the intestine, via antiapoptotic and pro-proliferating pathways, to guarantee mucosal integrity, energy absorption and motility. Further, it possesses anti-inflammatory properties. Presently, cisplatin acute and chronic damages and GLP-2 protective effects were investigated in the mouse distal colon using histological, immunohistochemical and biochemical techniques. The mice received cisplatin and the degradation-resistant GLP-2 analog ([Gly2]GLP-2) for 4 weeks. Cisplatin-treated mice showed mucosal damage, inflammation, IL-1β and IL-10 increase; decreased number of total neurons, ChAT- and nNOS-immunoreactive (IR) neurons; loss of SOX-10-IR cells and reduced expression of GFAP- and S100β-glial markers in the myenteric plexus. [Gly2]GLP-2 co-treatment partially prevented mucosal damage and counteracted the increase in cytokines and the loss of nNOS-IR and SOX-10-IR cells but not that of ChAT-IR neurons. Our data demonstrate that cisplatin causes mucosal injuries, neuropathy and gliopathy and that [Gly2]GLP-2 prevents these injuries, partially reducing mucosal inflammation and inducing ENS remodeling. Hence, this analog could represent an effective strategy to overcome colonic injures induced by cisplatin.

Highlights

Gastrointestinal (GI) toxicity is a common complication of platinum-based drug chemotherapy
We aimed to define whether cisplatin long-term administration induced mucosal lesions in the distal colon and whether these changes could be prevented by Glucagon-like peptide-2 (GLP-2) co-administration
We further investigated whether changes in neuronal population induced by cisplatin and the effects of GLP-2 upon enteric neurons were associated with specific neuronal subpopulations, i.e., the cholinergic, nitrergic and vipergic

Summary

Introduction

Gastrointestinal (GI) toxicity is a common complication of platinum-based drug chemotherapy. Nausea, vomiting, constipation and diarrhea are likely to occur within a few hours/days following the treatment (acute toxicity) and can persist up to 10 years after the treatment has ceased (late/chronic toxicity) [1]. It can lead to delay in treatment cycles and dose reduction that, can impact the patient’s response to treatment and risk of relapse. Cisplatin, one of the most effective and widely used drugs in standard treatments of several solid cancers, causes early and late GI side effects. Cisplatin-induced mucosal damage likely has a significant role in the acute toxicity, whereas the pathophysiology of the cisplatin-induced chronic long-lasting side effects is still unclear [2,4]

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