Neuron Enteric Death Is Mediated by S100B During Intestinal Mucositis Induced by 5‐Fluorouracil

Abstract

The goal of this study was to investigate whether S100B is involved in 5‐FU‐induced enteric neuron death during intestinal mucositis. This study was approved by ethical committee of Federal university of Ceará (protocol n° 80/2015). Intestinal mucositis was induced by injecting a single dose of 5‐FU (450 mg/kg, IP) and the mice were euthanized after 3 days. The mice were pretreated with Pentamidine, an S100B inhibitor, (4 mg/kg daily) for three days. The animals were euthanized and small intestine tissues (duodenum, jejunum and ileum) were collected to evaluate S100B expression by Western Blot, enteric neuron alterations by immunohistochemistry for HuC/D (neuron marker), neuronal death by TUNEL Assay and double staining of HuC/D with RAGE or NFκB NLS. A primary culture of enteric neuron from the small intestine was performed to evaluate the direct effect of 5‐FU and S100B in neuron death using a TUNEL assay. 5‐FU reduced (p<0.01) HuC/D protein expression and increased (p<0.01) S100B protein expression in the small intestine, as well as increased (p<0.01) TUNEL positive cells on jejunum of mice compared with control group. 5‐FU enhanced RAGE and NFκB NLS immunostaining in enteric neurons in the jejunum compared to control group. Pentamidine prevented (p<0.01) these alterations induced by 5‐FU in the intestine. Higher S100B concentration, but not 5‐FU, directly caused (p<0.0001) enteric neuron death. This study showed an important role for enteric glia cells in 5‐FU‐induced enteric neuron death via S100B, during intestinal mucositis. Our results suggest that enteric glial cells release S100B, which in turn activates NFκB signaling through RAGE activation in neurons, leading to neuronal cell death during intestinal mucositis induced by 5‐FU. Therefore, the S100B signaling pathway appears to be a promising pharmacological target to prevent 5‐FU‐induced enteric neuron death.Support or Funding InformationPROCAD/CAPES, CNPq, FUNCAPThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.