Troxerrutina previne alterações morfológicas na mucosite intestinal induzida por 5-fluorouracil: papel da via ciclooxigenase-2

Abstract

Intestinal mucositis is a common complication associated to 5-Fluorouracil (5-FU) treatment, a chemotherapeutic agent widely used for cancer treatment. Troxerrutin (TRX) a semisynthetic flavonoid from the rutin, which is extracted from the Dimorphandra gardneriana, which has various pharmacological activities described as antioxidant and antiinflammatory. The aim of the present study was to evaluate the effect of TRX on intestinal mucositis induced by 5-FU in Swiss mice. The animals were randomly divided in groups: Saline, 5-FU, TRX (50, 100 and 150 mg/kg), Celecoxib (CLX), CLX + TRX 100 mg/kg. The mice weight was evaluated daily for each group. At the end of the experimental protocol, the animals were euthanized and segments of the small intestine (duodenum, jejunum and ileum) were collected for histopathological and morphometric evaluation; leukogram, reduced glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO), mast cell and goblet counts, and cyclooxygenase 2 (COX-2) by immunohistochemistry. In silico molecular docking assays of the complexes formed between TRX and the COX, TNF-α and NF-kB enzymes were performed. The results indicate that 5-FU induced intense weight loss, reduced villi height, causing loss of crypt architecture, edema, inflammatory infiltrate as well as increased MPO and MDA and decreased GSH, and induction of mastocytosis and depletion of goblet cells. The use of TRX 100 mg/kg prevented histopathological changes induced by 5- FU, showing a decrease of MDA and MPO levels, increased GSH concentration, prevented intestinal mastocytosis and prevented depletion of goblet cells. Through modulation of the COX-2 pathway, can be evidenced by morphometric and histopathological and immunohistochemical evaluation for COX-2 that TRX 100 mg/kg possibly acts interacting with COX-2 pathways to trigger its protective effect on intestinal mucositis. The findings in this study suggest that TRX (100 mg/kg) prevented the morphological changes induced by 5- FU, possibly related to COX-2 pathways.