Efeito do derivado antraquinônico 1-Metoxi-4-((2-Hidroxitetradecil)Amino)-Antraceno-9,10-Diona (MTA), análogo a mitoxantrona, na modulação da resposta imune em modelo de encefalomielite autoimune experimental

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease that affects the central nervous system (CNS). The experimental autoimmune encephalomyelitis (EAE) is an animal model for the study of MS. Mitoxantrone (MIT) is an agent used for treatment of MS, however, the cardiotoxicity is a cumulative adverse effects of treatment. This study investigated the effect of the new derivative anthraquinone, 1-methoxy-4 - ((2-hydroxytetradecyl) amino) anthracene-9,10-dione, called MTA in EAE model. C57BL/6 mice were immunized with the peptide of myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37RA and treated with 1 mg/kg of MIT or MTA the day 14 to day 20 post-immunization. The toxic effects arising from treatment with MTA and MIT after 7 days of treatment in C57BL/6 mice immunized were analyzed using survival curves, body weight and serum protein CK-MB. At day 21 after immunization, the spinal cords were removed and subjected to analysis such as determination of pro-inflammatory cytokines IFN-γ, IL-17, IL-6 and regulatory cytokines IL-10 and TGF-β and CCL5, CCL20 chemokines using ELISA, cellular phenotype through expression of markers CD4, CD8, CD19, CD11b, CD11c, F4/80 by flow cytometry and the presence of inflammatory infiltrates and demyelination by histopathology. Treatment with MTA reduced the clinical score of the disease in C57BL /6 mice immunized with MOG35-55, which was associated with the reduction of demyelination, presence of pro-inflammatory cells, release of cytokines IL-17, IFN-γ, IL-6 and increased of IL-10 and TGF-β in the spinal cord, as well as the MIT. However, treatment with MIT reduced survivability, the body weight and further increased the production of CK-MB in serum protein, suggesting cardiac muscle stress during the treatment, which was not observed in the MTA group. The results suggest an important role of MTA in modulating the immune response involved in MS. The attenuation of inflammation and thereby reduce the clinical score involving the reduction of pro-inflammatory cytokines indicate this compound as an alternative treatment for autoimmune diseases in the central nervous system.