EFFECT OF TELMISARTAN IN ORAL MUCOSITE INDUCED BY 5-FLUOROURACIL IN HAMSTERS
Oral mucositis; Inflammation; 5-Fluorouracil; Telmisartan.
Oral mucositis (OM) is a debilitating side effect often present in patients undergoing cancer treatment. This study aims to evaluate the anti-inflammatory effects of Telmisartan (TELM), an angiotensin II receptor antagonist, in an experimental model of oral mucositis induced by 5-fluorouracil (5-FU) in hamsters. During the 10 days, the animals were treated with Telmisartan at doses of 1, 5 and 10mg/Kg. The animals received intraperitoneal injection of 5-fluorouracil on 1th and 2th day, at doses of 60 and 40 mg/Kg, respectively, and had their right jugual pouch everted and scratched superficially on the 4th day. The animals were euthanized on day 10 and blood and mucosa samples were collected. Mucosa were evaluated clinically by assigning a score after macroscopic analysis. At the end of the experiment the oral mucosa of the animals and the samples of both groups were evaluated according to histopathological and biochemical parameters. Levels of IL-1β, TNF-α and MDA were determined by the ELISA. Histopathological analyzes by HE and immunohistochemistry for MMP-9, COX-2 and TGF-β, as well as protein expression for SMAD 2/3 and TGF 1/2 by Western blot and RT-PCR for ELK1, STAT1, PI3K and NF-κB/p65. Analysis of variance ANOVA, followed by the Bonferroni test, was used to calculate differences between groups (p < 0,05). The results demonstrated that Telmisartan at 5 and 10 mg / kg reduced the anti-inflammatory effects of OM, due to the decrease in the levels of proinflammatory cytokines TNF-α and IL-1β (p < 0,05), MDA (p < 0,05), macroscopic and histopathological scores (p < 0,05), decreased immunostaining for MMP-9, COX-2 and TGF-β and protein expression of SMAD 2/3 and TGF 1/2. The 5 and 10 mg/Kg doses contributed to reduce the damage and inflammation induced oral mucositis induced by 5-FU, and the dose of 10 mg/Kg presented the best dose-response relationship.