Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil.
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil.
Sci Rep. 2019 Jan 24;9(1):665. doi: 10.1038/s41598-018-36878-z.
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.
5-氟尿嘧啶（5-FU）是一种抗癌药物，其主要副作用包括与肠道蠕动改变相关的肠道粘膜炎，可能是由于对肠神经系统（ENS）的影响，但潜在机制尚不清楚。在本报告中，我们使用动物模型研究了 S100B/RAGE/NFκB 途径在 5-FU（450mg/kg，IP，单次剂量）引起的肠道粘膜炎和肠神经毒性中的参与。5-FU 诱导的肠道损伤表现为绒毛缩短、隐窝结构丧失和强烈的炎症细胞浸润，以及小肠中 GFAP 和 S100B 共表达增加和 HuC/D 蛋白表达减少。此外，5-FU 增加了肠道神经元中 RAGE 和 NFκB NLS 免疫染色，与小肠中硝酸盐/亚硝酸盐、IL-6 和 TNF-α水平、iNOS 表达和 MDA 积累的显著增加相关。我们提供的证据表明，5-FU 以 S100B/RAGE/NFκB 依赖的方式诱导反应性神经胶质增生和肠神经元减少，因为 S100B 抑制剂戊脒可预防 5-FU 诱导的神经元丢失、肠神经胶质激活、肠道炎症、氧化应激和组织学损伤。
