MILTEFOSINA (HEXADECILFOSFOCOLINA) INDUZ DANOS GENÔMICOS MODULADOS PELO ANTIOXIDANTE ÁCIDO ASCÓRBICO.

Abstract

Leishmaniasis is a group of neglected non-contagious, parasitic and chronic infectious diseases caused by protozoa of the genus Leishmania. Visceral leishmaniasis is currently reported in 102 countries. Brazil has high rates of disease cases, registering only in a decade (2008 to 2017), 37,639 cases and 2,735 deaths. Due to increased relapses to first-choice antileishmanial drugs, since 2002, miltefosina has been introduced as oral treatment in countries such as India, Bangladesh and Nepal. However, little is known about the action of the drug and its interaction with the genetic material. Thus, in this study the genotoxic and mutagenic effect of this drug was evaluated, as well as the cellular and molecular mechanisms involved in its antileishmanial action. For this, in vitro and in vivo assays were performed to evaluate the ability of miltefosina to induce genomic instability, to increase the frequency of micronuclei and to cause cell death. Furthemore, the parasite load was also determined in infected animals and treated with antileishmanial, as well as was evaluated the antigenotoxic effect of ascorbic acid, recognized antioxidant, in animals treated with miltefosina under different treatment conditions (single and repeated doses, simultaneous, pre and post treatment). In addition, the activity of the antioxidant enzymes SOD, CAT and GPx and the expression of genes related to the DNA repair system (OGG1, MUTYH, NUDT1) were determined in order to identify possible molecular mechanisms related to the action of miltefosina. We initially demonstrated that miltefosina causes genomic lesions by oxidation of purine and pyrimidine bases of DNA, as well as inducing apoptosis and necrosis in mammalian cells. Subsequently, we verified that this damage can be modulated by ascorbic acid and that the antioxidant does not interfere with the antileishmanial efficacy of the drug. Finally, we verified that, in response to oxidative stress, the cell responds by increasing the activity of the SOD enzymes and the expression of the OGG1 repair gene.