Multiple Sclerosis (MS) is an autoimmune inflammatory disease directed against myelin proteins of the brain and spinal cord and is the most common human demyelinating disease of the central nervous system (CNS) that afflicts 1.4 million worldwide. A large number of cytokines and chemokines play pivotal roles in the establishment and maintenance of autoimmune disorders, acting in highly complex networks, and different cell types often exert overlapping and in part redundant functions. Mitoxantrone (MIT), approved for the treatment of several forms of MS in the United States of America and Europe, is an anthracene-based anticancer agent whose efficacy in treating MS is believed to be due to inhibition of the proliferation of T cells, B cells, and macrophages. The treatment with MIT, depending on the total cumulative dose, causes several side effects, such as the development of chronic cardiotoxicity.  Therefore, there is a need to develop effective and less toxic drugs with particular reference to cardiotoxicity. In this study, we investigate the clinical and immunological effects of N,N´-didodecanoyl-1,4-diaminoanthraquinone [DDAAQ], a lipophilic mitoxantrone analogue, on the myelin MOG-induced Experimental Autoimmune Encephalomyelitis (EAE) model.

The immunized mice presented EAE signs such as weakness or paralysis of their tail and limbs as well as loss of body weight, which became apparent around days 10-12 following immunization. Intraperitoneal injections of DDAAQ demonstrated to be effective in treating EAE mice, showing, from day 16, pronounced differences in clinical score when compared to immunized EAE mice. DDAAQ treated group showed an increase of IL-17 and IL-10 production and a decrease of IFN-γ, IL-12p40 and CCL5 release at CNS. Our results suggests that increases of IL-17 and IL-10 production after DDAAQ treatment, could be related to a decrease in pro-inflammatory cytokines such as IFN-, IL-12 and Th1 profile chemokines (CCL5), suggesting that DDAAQ treatment induces an immunoregulatory profile newly characterized by Th17 regulatory cells.

The presents results suggests that the major mechanism responsible for clinical effects of this compound are nonspecific citotoxicity action on lymphocytes and immunological mechanisms such as activation of Th17 regulatory cells and the reduction of cellular enrollment for CNS. However, additional studies are necessary to verify the efficacy, safety and toxicological risk in MS.