Abstract
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.
Highlights
Figure 1. 5-FU upregulates S100B and NFκB p65 protein expression and increases GFAP and S100B coexpression in the intestine. (A) Representative Western Blot images showing S100B and beta-actin protein expression
We provide the first evidence of the deleterious effect of S100B on 5-FU-induced intestinal mucositis pathogenesis
We showed that S100B is produced by EGCs and may be involved in enteric neuron death and reactive gliosis during mucositis as well as in the histological alterations, animal weight loss, inflammatory response and oxidative stress through a receptors for advanced glycation endproducts (RAGE)/NFκB-dependent mechanism
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. Qualitative analysis showed that 4 mg/kg pentamidine decreased (P < 0.01) GFAP and S100B immunostaining in the mucosal, submucosal and myenteric plexuses of the jejunum compared to the 5-FU group (Fig. 3A) To confirm these results, we measured GFAP and S100B mRNA levels by qPCR. GFAP expression was 19-fold higher in 5-FU-treated mice than in controls (P < 0.01), whereas pentamidine induced a 10.5-fold decrease (P < 0.01) in GFAP mRNA levels in the jejunum compared to the 5-FU group (Fig. 3D). The treatment with pentamidine alone, caused no changes on S100B expression compared with control group (Fig. S4), Taken together, these results show that S100B inhibition with pentamidine diminish glial activation in 5-FU-induced intestinal mucositis due to decreased levels of S100B and GFAP in the jejunum.
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