Potencial terapêutico da pterocarpanoquinona LQB-118 na infecção pelo Trypanosoma cruzi

Abstract

Chagas disease is caused by Trypanosoma cruzi and endemic in Latin America, especially in Brazil. The therapy available for the disease is very limited and present effective only for acute cases of Chagas disease. The pterocarpanquinone LQB-118 shows antitumor and antileishmanial activities. Preliminary studies in our group indicated that LQB-118 shows trypanosomicidalactivity on intracellular amastigotes of T. cruzi (Dm28c) and in vivo, the oral treatment was able reduce parasitemia in mice infected with T. cruzi (Y strain) and maintain normal creatine kinase levels. The aim of this thesis was to evaluate the therapeutic potential of LQB-118 inT. cruzi (Y strain) experimental infection, with emphasis in the chronic phase of infection. Epimastigotes, blood trypomastigotes and amastigotes of T. cruzi (Y strain) were incubated in the presence or absence of LQB-118. In order to induce the acute phasein vivo, Swiss Webster mice were infected with intraperitoneally 103 bloodstrem trypomastigotesand treated orally with LQB-118 (40 mg/Kg /day) for 12 days starting 4º dpi. For the chronic phase, Swiss Webster mice were infected intraperitoneally with102 bloodstream trypomastigotes with LQB-118 (20 mg/Kg /2 x day ) for 15 days starting at 31º dpi. Parasitemia, survival rate and histopathology of the heart were evaluated. LQB-118 demonstrated inhibitory activity on the three evolutionary forms of the parasite, with IC50 estimated at 1.82μM ± 0.17 (96h), 16.9μM ± 1.6 (24h) and 3.96μM ± 1.06(48h) for epimastigotes, bloondstream trypomastigotes and intracellular amastigotes, respectively. In vivo, in the acute phase, LQB-118 reduced the parasitemia in the 11th and 12th dpi by 49.5 % (p<0.02) and 41.14%, respectively, in relation to the untreated group, with tendency to reduce the number of amastigote nests, but without difference in inflammatory infiltrate and myocyte degradation. In the chronic phase, there wasno difference in the of the intensity inflammatory infiltrate in the heart of infected animals and treated or no with LQB-118. However, there was a reduce at 34.6% reductionof collagen in the cardiac tissue of treated animals in comparison to animals without treatment. The presence of parasites in the cardiac tissue of LQB-118-treated animal was rare, with 22% (2/9) for LQB-118-treated animals and at 10% (1/10) forum treared animals. Our results indicate that the pterocarpanoquinone LQB-118 has trypassomicid activity against T. cruzi (strain Y) both in vitro and in vivo representing a promising therapeutic action in both the acute and chronic phases of Chagas disease.