Gliclazide Prevents 5-FU-Induced Oral Mucositis by Reducing Oxidative Stress, Inflammation, and P-Selectin Adhesion Molecules

Cristiane Assunção da Costa Cunha Mafra; Roseane Carvalho Vasconcelos; Caroline Addison Carvalho Xavier de Medeiros; Renata Ferreira de Carvalho Leitão; Gerly Anne de Castro Brito; Deiziane Viana da Silva Costa; Gerlane Coelho Bernardo Guerra; Raimundo Fernandes de Araújo Jr; Aldo Cunha Medeiros; Aurigena Antunes de Araújo

doi:10.3389/fphys.2019.00327

Gliclazide Prevents 5-FU-Induced Oral Mucositis by Reducing Oxidative Stress, Inflammation, and P-Selectin Adhesion Molecules

Front Physiol. 2019 Mar 26:10:327. doi: 10.3389/fphys.2019.00327. eCollection 2019.

Affiliations

¹ Postgraduate Programs in Oral Science, Department of Biophysics and Pharmacology, Federal University of Rio Grande Norte, Natal, Brazil.
² Postgraduate Program in Public Health, Department of Biophysics and Pharmacology, UFRN, Natal, Brazil.
³ Department of Biophysics and Pharmacology, UFRN, Natal, Brazil.
⁴ Postgraduate Program in Biological Science and Rede Nordeste de Biotecnologia/Renorbio, Federal University of Rio Grande Norte, Natal, Brazil.
⁵ Postgraduate Programs in Pharmacology and Morphology, Department of Morphology/Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
⁶ Postgraduate Programs in Postgraduate Program in Biological Science/Pharmaceutical Science, Department of Biophysical and Pharmacology, UFRN, Natal, Brazil.
⁷ Postgraduate Programs in Functional and Structural Biology and Health Science, Department of Morphology, UFRN, Natal, Brazil.
⁸ Postgraduate Programs in Health Science, Department of Surgery, UFRN, Natal, Brazil.
⁹ Postgraduate Oral Science, Postgraduate Programs in Pharmaceutical Science, Department of Biophysics and Pharmacology, Federal University of Rio Grande Norte, Natal, Brazil.

Abstract

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 (COX₂, 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) (p < 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) (p < 0.01). Treatment with gliclazide 10 mg/kg reduced MPO activity (p < 0.001), MDA levels (p < 0.001) and NFκB NLS P50 (p < 0.05) protein levels, resulting in low immunostaining to Cox-2, iNOS (p < 0.05), NFκB P65 (p < 0.05), and negative immunoreaction to MMP-2 (p < 0.001). However, it appeared that for Gpx1, the staining was restored in the GLI 10-FUT group compared with 5FUT/saline (p < 0.05). Immunofluorescence revealed decreased levels of P-selectin (p < 0.001) after treatment with gliclazide 10 mg/kg (p < 0.05). In summary, gliclazide accelerated mucosal recovery and reduced oxidative stress and inflammation in the 5-FU-induced OM in hamsters.

Keywords: 5-fluorouracil; gliclazide; inflammation; oral mucositis; oxidative stress.