Reposicionamento de fármacos: avaliação da atividade da atorvastatina sobre a homeostase intestinal.

Abstract

Mucositis is an adverse effect of cancer treatment regimens. Patients generally present diffuse ulcerative lesions, inflammation and hemorrhages throughout the gastrointestinal tract that promote secondary infectious complications, generating an important socioeconomic impact with increased morbidity and mortality. Treatment for mucositis is limited and aims to prevent complications, including pain control, nutritional support and prevention of secondary infections with prophylactic measures. Pharmacological repositioning focuses on the reuse of known compounds for other purposes and has been an alternative to boost drug discovery and reduce obstacles associated with the process of developing new compounds. Statins, which are lipid-lowering agents, have "pleiotropic" effects that include anti-inflammatory, antioxidant and immunomodulatory properties, and may be an alternative to aid in the treatment of mucositis. In this study, we aimed to evaluate the therapeutic potential of atorvastatin in a murine model of gastrointestinal mucositis induced by 5-fluorouracil (5-FU). Initially, a systematic literature review was carried out to search the literature for studies applying statins to inflammatory bowel diseases. Secondly, a preclinical model of gastrointestinal mucositis using BALB/c mice was carried out. The animals were divided into six experimental groups and treated with atorvastatin (5, 10 and 30 mg/kg) administered via oral gavage. To induce mucositis, the animals received intraperitoneal injections of 5-FU (30 mg/kg/day) for 5 days. The results obtained from the systematic review demonstrated that 21 relevant studies in preclinical models using various colitis induction protocols and various statins demonstrated numerous beneficial effects of these drugs in reducing disease activity, inflammatory profile, oxidative stress and general clinical parameters in animals. . In the preclinical model of mucositis developed in this study, treatment with atorvastatin improved the function of the epithelial barrier, promoting a reduction in intestinal permeability, also associated with an improvement in the architecture of the small intestine mucosa, reduction of inflammatory infiltrate and oxidative stress. Atorvastatin also downregulated inflammatory markers such as Tlr4, MyD88, NF-κB, Tnf-a, Il1β and Il6 in a dose-dependent manner and upregulated the mRNA levels of mucin 2 (MUC2), ZO-1, occludin and tight junction proteins. The results also demonstrated that atorvastatin at doses of 5 and 10 mg/kg had a protective role for the liver, reducing the levels of AST, ALT, oxidative stress and increasing the uptake of 99mTc-phytate in the hepatic region. In conclusion, the results suggest that atorvastatin may be an alternative to minimize the toxic adverse effects of 5-FU, involving the inhibition of the TLR4/MYD88/NPRL3/NF-κB, iNos and caspase 3 signaling pathways and being able to prevent adverse damage to the intestinal mucosa and liver, proving to be a therapeutic strategy to help treat intestinal mucositis.