5-Fluorouracil Induces Enteric Neuron Death and Glial Activation During Intestinal Mucositis via a S100B-RAGE-NFκB-Dependent Pathway

Autor: Richard L. Guerrant, Deiziane Viana da Silva Costa, Gerly Anne de Castro Brito, David T. Bolick, Vivaldo Moura-Neto, Angeline M. H. P. Silva, Conceição da Silva Martins, Ana Carina Bon-Frauches, Patricia Castelucci, Gutierrez B. Freitas, Roberto C. P. Lima-Júnior, Renata Ferreira de Carvalho Leitão, Cirle A. Warren
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Mucositis
Crypt
Receptor for Advanced Glycation End Products
Down-Regulation
lcsh:Medicine
S100 Calcium Binding Protein beta Subunit
medicine.disease_cause
Article
Enteric Nervous System
RAGE (receptor)
03 medical and health sciences
Mice
0302 clinical medicine
Glial Fibrillary Acidic Protein
medicine
Animals
Intestinal Mucosa
lcsh:Science
Mucosite
Multidisciplinary
Cell Death
Chemistry
lcsh:R
Neurotoxicity
NF-kappa B
Transcription Factor RelA
Motilidade Gastrointestinal
medicine.disease
Small intestine
Oxidative Stress
030104 developmental biology
medicine.anatomical_structure
NEOPLASIAS
Cancer research
Cytokines
Enteric nervous system
lcsh:Q
Fluorouracil
Gastrointestinal Motility
Fluoruracila
Neuroglia
030217 neurology & neurosurgery
Immunostaining
Oxidative stress
Zdroj: Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019)
Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
Scientific Reports
Repositório Institucional da Universidade Federal do Ceará (UFC)
Universidade Federal do Ceará (UFC)
instacron:UFC
ISSN: 2045-2322
DOI: 10.1038/s41598-018-36878-z
Popis: 5-Fluorouracil (5-FU) is an anticancer agent whose main side effects include intestinal mucositis associated with intestinal motility alterations maybe due to an effect on the enteric nervous system (ENS), but the underlying mechanism remains unclear. In this report, we used an animal model to investigate the participation of the S100B/RAGE/NFκB pathway in intestinal mucositis and enteric neurotoxicity caused by 5-FU (450 mg/kg, IP, single dose). 5-FU induced intestinal damage observed by shortened villi, loss of crypt architecture and intense inflammatory cell infiltrate as well as increased GFAP and S100B co-expression and decreased HuC/D protein expression in the small intestine. Furthermore, 5-FU increased RAGE and NFκB NLS immunostaining in enteric neurons, associated with a significant increase in the nitrite/nitrate, IL-6 and TNF-α levels, iNOS expression and MDA accumulation in the small intestine. We provide evidence that 5-FU induces reactive gliosis and reduction of enteric neurons in a S100B/RAGE/NFκB-dependent manner, since pentamidine, a S100B inhibitor, prevented 5-FU-induced neuronal loss, enteric glia activation, intestinal inflammation, oxidative stress and histological injury.
Databáze: OpenAIRE
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