Ação terapêutica e moduladora da quercetina na leishmaniose tegumentar experimental por Leishmania braziliensis e Leishmania major

Abstract

Tegumentary leishmaniasis is the most frequent form of leishmaniasis in Brazil, with Leishmania (Viannia) braziliensis, which causes the cutaneous and mucosal clinical forms, where there is an intense and destructive inflammatory response in the oronasal region. The therapeutic arsenal is restricted, toxic and in some situations ineffective. It is important to study new molecules with therapeutic potential for leishmaniasis. The flavonoid quercetin has biological activities, including actions: anti-inflammatory, antioxidant, pro-oxidant, immunomodulatory and antiparasitic. In trypanosomatids its action is reported. The objective of this study was to evaluate the therapeutic and immunomodulatory activity of quercetin in experimental models of infection with L.braziliensis (hamster) and L.major (in mice), since in the latter the well-established immune response profiles associated with susceptibility (BALB / c) and resistance (C57BL/ 6). The in vitro effect was evaluated on the growth of intracellular promastigotes and amastigotes of L.braziliensis and L. major. Modulation of macrophages was evaluated by the production of reactive oxygen species (ROS) using the H2DCFDA and Amplex red probes and the cytometric flow cytometry (CBA) production. In vivo treatment of the animals was done via the oral (gavage) 5 times a week with 20mg / kg / 40mg / kg and started after 7 days of infection or with the lesion established for 7-10 weeks. In amastigotes of L.braziliensis and L.major, quercetin promoted inhibition in the infection index. Pretreatment of macrophages has reduced the rate of infection. Macrophage treated for 48 h showed increased ROS and H2O2 production with 330 μM quercetin and when infected and treated for 48 h, increased yield by being dose-dependent. There was a decrease in IL-6 and TNF levels and an increase in IL-10 and MCP-1. In vivo, treatment of hamsters with 20 mg / kg quercetin reduced the size of the lesion and the parasitic load. Treatment after established injury did not control lesion size, but decreased parasitic load. In BALB/ c infected with L.major, treatment with 20 mg / kg quercetin reduced parasite load and treatment with 40 mg / kg reduced lesion and parasitic load. There was an increase in the production of IL-2, IL-4 and IL-6 by splenic lymphocytes. In C57BL / 6, treatment with 40 mg / kg quercetin reduced the parasite load and increased production of IL-10, IL-17, IFN-γ and TNF. These results show that the flavonoid quercetin shows antiparasitic activity in L.braziliensis and L.major, stimulating ROS production by macrophages while modulating it to an anti-inflammatory state. Oral therapeutic action with no signs of hepatic and renal toxicity for the animals demonstrates the promising potential of quercetin in the therapy of leishmaniasis.