Investigação da atividade anti-inflamatória de derivados da atorvastatina em macrófagos RAW 264.7

• Autor(a) principal: Santos, Najara Gomes dos
• Data de Publicação: 2017
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/16306
• topic: Inflammation; Statins; Pleiotropic Effects; Immunomodulation; Inflamação; Estatinas; Efeitos Pleiotrópicos; Imunomodulação; Inflamação; Inibidores de Hidroximetilglutaril-CoA Redutases; Imunomodulação; CNPQ::CIENCIAS BIOLOGICAS::BIOFISICA

Inflammatory diseases constitute a heterogeneous and complex group of diseases that are an important cause of morbidity and mortality in the world. This fact increasingly instigates the reasearch for effective and safe therapeutic alternatives. Statins are bioactive compounds that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme responsible for cholesterol synthesis regulation. By this mean, acts to reduce the levels of tecidual cholesterol and are used as drugs in patients with hypercholesterolemia. However, HMG-CoA reductase inhibiting, these molecules reduce the synthesis of various isoprenoids because it also interrupts the mevalonate/mevalonic acid, generating some of the pleiotropic effects of these molecules. The atorvastatin derivatives tested (PCSR09.001, PCSR08.002, PALP 002/13 F and PALP 005/13 JBC) were developed as antiparasitics. Due to the presence of portions with known anti-inflammatory action in their chemical structure, it was used in order to investigate anti-inflammatory activity and toxicity. To do so, in vitro tests were performed to analise cell viability (cell viability assay with WST-1); proliferation and activation of RAW 264.7 macrophages (WST-1 modified assay), analysis of cytokines and cell surface markers involved in inflammation, as well as migration, death, and cell cycle. According to the results, PCSR09.001 and PALP 002/13 F did not present cytotoxicity (p <0.05) for RAW 264.7 macrophages, whereas PCSR08.002 presented cytotoxic effects to cells only in the largest concentration tested and PALP 005/13 JBC was cytotoxic at concentrations of 10, 100 and 1000 μM. Considering the Stimulation Index in the modified WST-1 assay - at the concentration where most of the derivatives showed no citotoxicity (100 μM) - PCSR08.002 and PCSR09.001 were the most effective, followed by PALP 002/13 (p < 0.05). Cytokine amount and expression of surface markers have suggested that PCSR08.002 molecule is the one that best modulates inflammation. Data obtained through flow cytometry and cell migration assay have shown that PCSR08.002 and PCSR09.001 derivatives, at concentrations of 100 μM and 10 μM, respectively, indicate the lower levels of apoptosis and the greater inhibition of macrophage migration.