Mafra Cristiane Assunção da Costa Cunha, Vasconcelos Roseane Carvalho, de Medeiros Caroline Addison Carvalho Xavier, Leitão Renata Ferreira de Carvalho, Brito Gerly Anne de Castro, Costa Deiziane Viana da Silva, Guerra Gerlane Coelho Bernardo, de Araújo Raimundo Fernandes, Medeiros Aldo Cunha, de Araújo Aurigena Antunes
Postgraduate Programs in Oral Science, Department of Biophysics and Pharmacology, Federal University of Rio Grande Norte, Natal, Brazil.
Postgraduate Program in Public Health, Department of Biophysics and Pharmacology, UFRN, Natal, Brazil.
Front Physiol. 2019 Mar 26;10:327. doi: 10.3389/fphys.2019.00327. eCollection 2019.
Oral mucositis (OM) is one of the main side effects of the head and neck cancer treatment, particularly radiotherapy and/or chemotherapy. OM is characterized by ulcers, erythema, dysphagia, xerostomia, and increased susceptibility to opportunistic infections. In the perspective of finding pharmacological therapies to prevent inflammation and ulceration of OM, the investigation of the pleiotropic effect of commercial drugs is needed, among them gliclazide, an antidiabetic drug. This study aimed to evaluate the effect of gliclazide in an experimental OM model induced by 5-fluorouracil. Male hamsters were pre-treated with oral gliclazide (1, 5, or 10 mg/kg) for 10 days. Cheek pouch samples were subjected to histopathological and immunohistochemical analysis (COX, iNOS, MMP-2, NFκB P65, GPx) and imunofluorescence (P-selectin). IL-1β and TNF-α levels, Myeloperoxidase activity (MPO) and malondialdehyde (MDA) levels were investigated by ultraviolet-visible spectroscopy analysis. NFκB NLS P50 protein levels were analyzed by western blotting. The group treated with gliclazide at a dose of 10 mg/kg showed presence of erythema, no evidence of erosion, and absence of mucosal ulceration with a score of 1 (1-2) ( < 0.01). Histopathological data for the group treated with gliclazide 10 mg/kg showed re-epithelialization, discrete mononuclear inflammatory infiltrate and absence of hemorrhage, edema, ulcers and abscesses with a score of 1 (1-1) ( < 0.01). Treatment with gliclazide 10 mg/kg reduced MPO activity ( < 0.001), MDA levels ( < 0.001) and NFκB NLS P50 ( < 0.05) protein levels, resulting in low immunostaining to Cox-2, iNOS ( < 0.05), NFκB P65 ( < 0.05), and negative immunoreaction to MMP-2 ( < 0.001). However, it appeared that for Gpx1, the staining was restored in the GLI 10-FUT group compared with 5FUT/saline ( < 0.05). Immunofluorescence revealed decreased levels of P-selectin ( < 0.001) after treatment with gliclazide 10 mg/kg ( < 0.05). In summary, gliclazide accelerated mucosal recovery and reduced oxidative stress and inflammation in the 5-FU-induced OM in hamsters.
口腔黏膜炎（OM）是头颈癌治疗的主要副作用之一，尤其是放疗和/或化疗。OM的特征是溃疡、红斑、吞咽困难、口干以及对机会性感染的易感性增加。从寻找预防OM炎症和溃疡的药物疗法的角度来看，需要研究商业药物的多效性作用，其中包括抗糖尿病药物格列齐特。本研究旨在评估格列齐特在5-氟尿嘧啶诱导的实验性OM模型中的作用。雄性仓鼠口服格列齐特（1、5或10mg/kg）预处理10天。对颊囊样本进行组织病理学和免疫组织化学分析（COX、iNOS、MMP-2、NFκB P65、GPx）以及免疫荧光分析（P-选择素）。通过紫外可见光谱分析研究白细胞介素-1β和肿瘤坏死因子-α水平、髓过氧化物酶活性（MPO）和丙二醛（MDA）水平。通过蛋白质印迹法分析NFκB NLS P50蛋白水平。以10mg/kg剂量格列齐特治疗的组出现红斑，无糜烂迹象，且无黏膜溃疡，评分为1（1 - 2）（<0.01）。以10mg/kg格列齐特治疗组的组织病理学数据显示上皮再形成、散在单核炎性浸润，且无出血、水肿、溃疡和脓肿，评分为1（1 - 1）（<0.01）。以10mg/kg格列齐特治疗可降低MPO活性（<0.001）、MDA水平（<0.001）和NFκB NLS P50（<0.05）蛋白水平，导致Cox-2、iNOS（<0.05）、NFκB P65（<0.05）免疫染色降低，以及MMP-2免疫反应阴性（<0.001）。然而，与5FUT/生理盐水组相比，在GLI 10 - FUT组中Gpx1的染色似乎恢复了（<0.05）。免疫荧光显示以10mg/kg格列齐特治疗后P-选择素水平降低（<0.001）（<0.05）。总之，格列齐特可加速仓鼠5-FU诱导的OM模型中的黏膜恢复，并降低氧化应激和炎症反应。
