Protective effect of angiotensin II receptor blocker against oxidative stress and inflammation in an oral mucositis experimental model

J Oral Pathol Med. 2018 Nov;47(10):972-984. doi: 10.1111/jop.12775. Epub 2018 Sep 19.

Abstract

Background: The aim of this study was to evaluate the effect of olmesartan medoxomil (Olme), an angiotensin II receptor antagonist, on oral mucositis (OM) experimental model.

Methods: Oral mucositis was induced in hamsters with 5-fluorouracil (5-FU; 60 mg/kg day 1 and 40 mg/kg day 2). Animals (n = 10/group) were pretreated with oral Olme (1, 5, or 10 mg/kg) or vehicle 30 minutes before 5-FU injection and daily, until day 10. Cheek pouch samples were subjected to histopathological and immunostaining analysis of IL-1β, TNF-α, IL-10, TGF-β, macrophage migration inhibitory factor (MIF), SOD, MMP-2 and FGF-2. In addition, IL-1β and TNF-α levels were evaluated by ELISA. Myeloperoxidase activity (MPO), glutathione (GSH) and malondialdehyde (MDA) levels were investigated by spectroscopic UV/VIS analysis. Reverse transcriptase polymerase chain reactions (RT-PCRs) were used to quantify the expression of IL-1β, TNF-α, NF-κBp65, MKP1 and ACE2. Inducible nitric oxide synthase (iNOS) and extracellular regulated kinase (ERK)1/2 protein levels were analysed by Western blot.

Results: Treatment with 10 mg/kg Olme reduced ulceration, inflammatory cell infiltration, MPO activity, MDA levels, iNOS and ERK1/2 proteins levels, MIF expression and TNF-α and IL-1β of levels and gene expression. These findings were associated with a significant increase in the immunostaining of IL-10, FGF-2 and TGF-β. In addition, gene expression of IL-1β, TNF-α, NF-κBp65 MKP1 and ACE2 was decreased.

Conclusion: Olmesartan at a dose of 10 mg/kg prevented the mucosal damage and inflammation associated with 5-FU-induced OM, increasing granulation and tissue repair.

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

MeSH terms

  • Angiotensin Receptor Antagonists / pharmacology*
  • Angiotensin Receptor Antagonists / therapeutic use*
  • Animals
  • Antimetabolites, Antineoplastic / adverse effects
  • Cricetinae
  • Cytokines / metabolism*
  • Fluorouracil / adverse effects
  • Inflammation Mediators / metabolism*
  • Male
  • Mesocricetus
  • Models, Animal
  • Olmesartan Medoxomil / pharmacology*
  • Olmesartan Medoxomil / therapeutic use*
  • Oxidative Stress / drug effects*
  • Stomatitis / chemically induced
  • Stomatitis / drug therapy*
  • Stomatitis / metabolism*

Substances

  • Angiotensin Receptor Antagonists
  • Antimetabolites, Antineoplastic
  • Cytokines
  • Inflammation Mediators
  • Olmesartan Medoxomil
  • Fluorouracil

Grant support