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

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

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 inves...

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Bibliographic Details
Published in:Scientific reports Vol. 9; no. 1; p. 665
Main Authors: Costa, Deiziane V. S., Bon-Frauches, Ana C., Silva, Angeline M. H. P., Lima-Júnior, Roberto C. P., Martins, Conceição S., Leitão, Renata F. C., Freitas, Gutierrez B., Castelucci, Patricia, Bolick, David T., Guerrant, Richard L., Warren, Cirle A., Moura-Neto, Vivaldo, Brito, Gerly A. C.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 24-01-2019
Nature Publishing Group
Subjects:
13/1
13/2
13/21
14/19
38/39
5-Fluorouracil
631/378/371
692/4020/1503/2746
692/4028/67/1059
82/51
82/80
Animal models
Cell death
Enteric nervous system
Glial fibrillary acidic protein
Gliosis
Humanities and Social Sciences
Inflammation
Interleukin 6
Intestinal motility
Mucositis
multidisciplinary
Neuronal-glial interactions
Neurotoxicity
NF-κB protein
Nitric-oxide synthase
Oxidative stress
Pentamidine
S100b protein
Science
Science (multidisciplinary)
Small intestine
Tumor necrosis factor-α
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Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-36878-z