Efeito da telmisartana no modelo de mucosite oral induzida por 5-Fluorouracil em hamsters Golden Syriam (Mesocricetus auratus)

Abstract

Oral mucositis (OM) is a debilitating side effect often present in patients undergoing cancer treatment, which affects the oral cavity or oropharynx. Lesions resulting from OM can compromise the quality of life of patients undergoing radiotherapy and / or chemotherapy, as well as contribute to the suspension of the cancer treatment protocol. 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 the 5-fluorouracil (5-FU) chemotherapy in hamsters. In the course of 10 days, groups of animals submitted to 5-FU were treated with telmisartan at doses of 1, 5 or 10 mg/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 jugal pouch everted and scratched superficially on the 4th day. The animals were euthanized on day 10 and blood and mucosa samples were collected. The mucosa was evaluated clinically, through the assignment of scores after macroscopic and histopathological analysis. TNF-α and IL-1β levels were determined by the ELISA. Immunohistochemical analyzes for MMP-9, COX-2 and TGF-β, immunofluorescence for iNOS and NF-κB/p65, protein expression for SMAD 2/3 by Western blot and RT-PCR for STAT1, PPAR-γ and NF-κB/p65 were performed. Blood samples were used to evaluate hepatic and renal function as well as for leukocyte count. The results showed that Telmisartan at doses of 5 or 10 mg/Kg prevented the inflammatory effects of OM, with a decrease in macroscopic and histopathological (p < 0,05) and proinflammatory cytokine levels TNF-α and IL-1β (p < 0,05). TELM at the dose of 10 mg/Kg decreased the immunostaining for MMP-9, COX-2 and TGF-β, reduced immunoexpression for iNOS and NF-κB/p65 and protein expression of SMAD 2/3. TELM at doses of 5 or 10 mg/Kg reduced the gene expression of STAT1 and NF-κB/p65 and increased PPAR-γ expression, compared to the 5-FU group. The groups treated with TELM at doses of 1, 5 or 10 mg/Kg did not show significant difference (p < 0,05) in liver and renal function levels and showed a decrease in the number of leukocytes when compared to the 5-FU group. Thus, the drug Telmisartan had a protective effect on MO induced in hamsters, however, further studies are still needed.