MILTEFOSINA EXERCE SUA AÇÃO LEISHMANICIDA ATRAVÉS DO RECEPTOR DE PAF

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

22/02/2011

RESUMO

Visceral leishmaniasis,that can be caused by Leishmania donovani, L. infantum and L. chagasi, is considered by the World Health Organization (WHO) one of six major public health problems worldwide and is fatal if untreated. Miltefosine (hexadecylphosphocolina), which was first used as treatment in patients with cancer, has been used as an effective oral drug in visceral leishmaniasis. There is a structural similarity between miltefosine and platelet activating factor (PAF). PAF acts by binding to the PAF receptor (PAFR) present in target cells. The mechanism by which the drug works is not well established, our hypothesis is that due to structural similarities between PAF and the drug, miltefosine uses the PAF receptor to bind to the cell. To test this hypothesis, we used wild type mice and mice deficient in PAFR (PAFR-KO). Initially we found that macrophages from wild type mice and PAFR-KO showed a similar profile of infection when infected with L. donovani. The in vitro infection experiments revealed that macrophages from wild type mice treated with miltefosine were more effective in controlling the growth of the parasites than macrophages from PAFR-KO mice. However, treatment with miltefosine did not induce the production of significant amounts of nitric oxide (NO), which may indicate a cytotoxic mechanism independent of NO. When assessing the effect of miltefosine on the activity of the enzyme arginase, our data showed that the treatment with the drug only did not alter the enzyme activity, but in combination with IFN-γ and LPS was capable of downregulate its activity. We found that the in vivo infection with L. donovani showed no differences in susceptibility between wild-type mice and PAFR-KO. We treated wild type mice and PAFR-KO orally from day 14 after infection with L. donovani for seven consecutive days at doses of 10 and 20mg/kg/day. Our data revealed that treatment of wild type mice led to a reduction in parasite load in the liver and spleen of these animals. Interestingly, PAFR-KO mice showed a higher parasite load in these organs. Our results indicate that part of the antileishmanial activity of miltefosine is mediated by the PAFR.

ASSUNTO(S)

leishmania donovani fator ativador de plaquetas. visceral leishmaniasis l donovani miltefosina paf. imunologia leishmaniose visceral

ACESSO AO ARTIGO

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