Novas opções terapêuticas para o tratamento das leishmanioses

Abstract

Leishmaniasis are neglected diseases caused by protozoa of the genus Leishmania, which compromise viscera causing visceral leishmaniasis (VL), skin and mucous membranes causing cutaneous leishmaniasis (CL). In most cases, current treatment protocols present toxicity and low effectiveness. In addition, these parasites are becoming more resistant to conventional treatment methods. This thesis is composed of three chapters referring to the study of new therapeutic options in the treatment of leishmaniasis. In the first chapter we evaluated the efficacy of lapachol in in vitro and in vivo models of cutaneous leishmaniasis and visceral leishmaniasis. Our results showed that lapachol has a low cytotoxicity on HepG2 cells, good anti-Leishmania activity and a favorable selectivity index (SI) against L. amazonensis promastigotes and L. infantum. Efficacy was also evaluated in intracellular amastigotes. Flow cytometry analyzes showed that lapachol induces death by apoptosis in Leishmania promastigotes. In vivo, the efficacy of lapachol was confirmed in a murine model of visceral and tegumentary leishmaniasis, reducing the parasite load in the liver, spleen and skin lesions. In the second chapter we evaluated the in vitro efficacy of isoflavonoids (xylopic acid, kaurenoic acid, (-)-α-bisabolol) and terpenes ((-)-duartine and (3R)-claussequinone). Among the substances tested, claussequinone was the most effective in L. infantum and L. amazonensis promastigotes and also showed good activity against intracellular amastigotes in L. infantum. The third chapter shows the activity of Synadenium carinatum latex lectin (ScLL) in in vitro and in vivo models of visceral leishmaniasis. ScLL showed low cytotoxicity on NIH fibroblasts and showed agglutinating activity on L. infantum parasites. In tests with intracellular amastigotes, ScLL reduced the percentage of infection both in tests in which the parasites were treated before infection and in tests in which macrophages were stimulated with lectin. In vivo, animals that received parasites treated with ScLL for 1 hour showed a significant difference in parasite load compared to the control group, both in the spleen and liver. Animals that were infected with L. infantum and received treatment 2 days after infection (dpi) showed a reduction in spleen parasite load compared to the untreated group. Animals that received 12 dpi treatment showed a reduction in the spleen and in the liver. Our results show that lapachol, (3R)-claussequinone and ScLL can be considered in the search for new therapeutic options for the treatment of leishmaniasis.