Avaliação de uma molécula com atividade antileishmanial para emprego no tratamento contra as leishmanioses

Abstract

Therapeutic strategies against leishmaniasis must be improved, given that the drugs present problems such as toxicity, high cost and/or increasing of parasites resistance. Thus, the research and discovery of new antileishmanial compounds that have activity against Leishmania spp., but low toxicity to mammalian hosts, become desirable. In this study, a naphthoquinone derivative called Flau-A or 2- (2,3,4-tri-O-acetyl-6-deoxy-β-L-galactopyranosyloxy) -1,4-naphthoquinone was evaluated against promastigotes and amastigotes of Leishmania amazonensis and L. infantum, species that cause cutaneous and visceral leishmaniasis, respectively, in Americas. The results showed that Flau-A was effective against parasites forms and presented low toxicity for mice and humans cells, with better results than amphotericin B, used as a control. The mechanism of action showed that the molecule acted in parasites mitochondria causing its death, and the treatment of infected macrophages and the inhibition of infection using pre-incubated parasites showed its therapeutic potential in vitro. Then, the in vivo efficacy of molecule was evaluated in a murine model infected with L. amazonensis or L. infantum, either in the free form or incorporated in a system of micelles formed from Poloxamer P407 (Flau-A / M). The results showed that treatment with Flau-A or Flau-A/M reduced the average diameter of the lesions caused by L. amazonensis and the parasitic load on the lesion (L. amazonensis), liver, spleen, draining lymph nodes and bone marrow; when compared to the other groups. Such animals developed a specific Th1 immune response to parasites, with high levels of IFN-gamma, IL-12, TNF-α, GM-CSF, in addition to IgG2a antibodies, associated with low levels IL-4, IL-10 and IgG1 antibodies. These animals also showed low toxicity, when compared to the other groups. Flau-A/M was more effective than the free molecule in the therapeutic response against the two species of Leishmania. Thus, the micellar formulation could be considered as a therapeutic candidate for the treatment against leishmaniasis.