Efeito de compostos ciclopaladados em formas promastigotas e amastigotas de Leishmania infantum
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Data
2018-07-06
Autores
Passalacqua, Thais Gaban [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
As leishmanioses são um grupo de doenças causadas por parasitos protozoários do gênero Leishmania e são transmitidas pela picada da fêmea infectada do inseto flebotomíneo. Segundo a Organização Mundial da Saúde, as leishmanioses estão distribuídas em áreas tropicais e subtropicais e são encontradas em 98 países da Europa, África, Ásia e América. São estimados 700 a um milhão de novos casos com 20 a 30 mil mortes anuais. A quimioterapia das leishmanioses é deficiente, tóxica e se baseia no uso de compostos antimoniais pentavalentes desenvolvidos na década de 40, os quais são tóxicos e apresentam ineficácia devido ao desenvolvimento de cepas resistentes. Desta forma, a busca por novos compostos antileishmaniais é importante. Pensando nisso, uma série de compostos ciclopaladados foram avaliados quanto ao seu potencial leishmanicida. Em ensaios in vitro, o composto CP2, cuja eficácia no tratamento da leishmaniose cutânea foi demonstrada pelo nosso grupo de pesquisa, apresentou atividade antipromastigota e amastigota de L. (L.) infantum, espécie causadora da leishmaniose visceral. O tratamento in vivo demonstrou a eficácia na diminuição da carga parasitária no fígado e baço (50%), sendo superior à anfotericina B. Adicionalmente, CP2 não apresentou efeitos tóxicos como revelado pelos marcadores bioquímicos ALP, AST, ALT e creatinina. Para tentar entender os possíveis mecanismos de ação de outro composto ciclopaladado, CP4, foram realizados ensaios de relaxamento utilizando a enzima topoisomerease IB de L. (L.) donovani, verificando-se que esse composto, também é capaz de inibir a enzima do parasito em concentrações submicromolares.
Leishmaniasis is a group of diseases caused by protozoan parasites of the genus Leishmania and are transmitted by the bite of the infected female of the insect phlebotomine. According to the World Health Organization, leishmaniasis is distributed in tropical and subtropical areas and are found in 98 countries in Europe, Africa, Asia and America. Seven hundred to one million of new cases are estimated with 20 to 30 thousand annual deaths. The chemotherapy for leishmaniasis is deficient, toxic and is based on the use of pentavalent antimony compounds developed in the 40´s, which are toxic and present ineffectiveness due to the development of resistant strains. In this way, the search for new anti Leishmania compounds is very important. Thinking about it, a series of cyclopalladated compounds were evaluated regarding to their leishmanicidal potential. In vitro assays with the CP2 compound, which efficacy in the treatment of cutaneous leishmaniasis was previously demonstrated by our research group, presented promastigote and amastigote activity against L. (L.) infantum, a species that causes visceral leishmaniasis. In vivo treatment demonstrated the efficacy in the reduction of the parasitic load in the liver and spleen (50%), being higher than amphotericin B. Additionally, CP2 did not exhibit toxic effects as revealed by the evaluation of the biochemical markers ALP, AST, ALT and creatinine. To try to understand the possible mechanisms of action of another compound ciclopaladado, the CP4, relaxation tests were carried out using the enzyme topoisomerease IB of L. (L.) donovani. It was verified that this compound is also able to inhibit the parasite enzyme in submicromolar concentrations.
Leishmaniasis is a group of diseases caused by protozoan parasites of the genus Leishmania and are transmitted by the bite of the infected female of the insect phlebotomine. According to the World Health Organization, leishmaniasis is distributed in tropical and subtropical areas and are found in 98 countries in Europe, Africa, Asia and America. Seven hundred to one million of new cases are estimated with 20 to 30 thousand annual deaths. The chemotherapy for leishmaniasis is deficient, toxic and is based on the use of pentavalent antimony compounds developed in the 40´s, which are toxic and present ineffectiveness due to the development of resistant strains. In this way, the search for new anti Leishmania compounds is very important. Thinking about it, a series of cyclopalladated compounds were evaluated regarding to their leishmanicidal potential. In vitro assays with the CP2 compound, which efficacy in the treatment of cutaneous leishmaniasis was previously demonstrated by our research group, presented promastigote and amastigote activity against L. (L.) infantum, a species that causes visceral leishmaniasis. In vivo treatment demonstrated the efficacy in the reduction of the parasitic load in the liver and spleen (50%), being higher than amphotericin B. Additionally, CP2 did not exhibit toxic effects as revealed by the evaluation of the biochemical markers ALP, AST, ALT and creatinine. To try to understand the possible mechanisms of action of another compound ciclopaladado, the CP4, relaxation tests were carried out using the enzyme topoisomerease IB of L. (L.) donovani. It was verified that this compound is also able to inhibit the parasite enzyme in submicromolar concentrations.
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Palavras-chave
Leishmaniose, Paladio, Enzima, Mecanismo de ação, Dano ao DNA