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Chagas' disease, caused by the protozoan Trypanosoma cruzi, is a major cause of cardiovascular disability in countries where it is endemic. Damage to the heart microvasculature has been proposed to be an important factor in the pathogenesis of heart dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor and exerts its effects via specific ET A and ET B receptors. A few studies have suggested a role for ET-1 and its receptors in the pathogenesis of Chagas' disease. We investigated the effects of treatment with bosentan, an ET A/ET B receptor antagonist, on the course of T. cruzi infection (Y strain) in C57Bl/6 mice. Treatment with bosentan (100 mg kg-1 day-1) was given per os starting day 0 after infection until sacrifice. Bosentan significantly increased myocardial inflammation, with no effects on parasitemia. Although the total number of nests was similar, a lower number of intact amastigote nests was found in the heart of bosentan-treated animals. Bosentan failed to affect the infection-associated increase in the cardiac levels of the cytokines IFN-g and TNF-a and the chemokines CCL2/MCP-1, CCL3/MIP-1a and CCL5/RANTES. In vitro, pre-incubation with ET-1 (0.1 µM) 4 h before infection enhanced the uptake of the parasites by peritoneal macrophages, and this effect was abrogated when macrophages were pre-treated with bosentan (1 µM) 15 min before incubation with ET-1. However, ET-1 did not alter killing of intracellular parasites after 48 h of in vitro infection. Our data suggest that bosentan-treated mice have a delay in controlling parasitism which is compensated for exacerbated inflammation. Infection is eventually controlled in these animals and lethality is unchanged, demonstrating that ET-1 plays a minor role in the protection against acute murine T. cruzi infection.

Hypnophilin and panepoxydone, terpenoids isolated from Lentinus strigosus, have significant inhibitory activity onTrypanosoma cruzi trypanothione reductase (TR). Although they have similar TR inhibitory activity at 10 μg/mL (40.3 μM and 47.6 μM for hypnophilin and panepoxydone, respectively; ~100%), hypnophilin has a slightly greater inhibitory activity (~71%) on T. cruzi amastigote (AMA) growth in vitro as well as on in vitro phytohemagglutinin (PHA)-induced peripheral blood mononuclear (PBMC) proliferation (~70%) compared to panepoxydone (69% AMA inhibition and 91% PBMC inhibition). Hypnophilin and panepoxydone at 1.25 μg/mL had 67% inhibitory activity onLeishmania (Leishmania) amazonensis amastigote-like (AMA-like) growth in vitro. The panepoxydone activity was accompanied by a significant inhibitory effect on PHA-induced PBMC proliferation, suggesting a cytotoxic action. Moreover, incubation of human PBMC with panepoxydone reduced the percentage of CD16+ and CD14+ cells and down-regulated CD19+, CD4+ and CD8+ cells, while hypnophilin did not alter any of the phenotypes analyzed. These data indicate that hypnophilin may be considered to be a prototype for the design of drugs for the chemotherapy of diseases caused by Trypanosomatidae.

In this study we compared two lines of #P. megistus$ which differed only by its laboratory maintenance time. PM1 (more than five generations in insectarium) and PM2 (one or two generations under laboratory conditions). The parameters studied were temperature (tp), humidity (hm), the weight/length ratios (nutritional status, w/l), isoenzyme electrophoresis at 7 locus (ME, GPI, LDH, ICD and alfa-GPD), as well as enzymatic activity of alfa-glycerophosphate dehydrogenase (alfa-GPD ac.), a crucial flight activity related enzyme. Insects were processed according to SCHOFIELD (1980) and observed througth a period of 30 days. The temperature and humidity were measured daily at the safe time, and the insects that had flighted, "good" flyers (gf), were also measured for the determination of the nutritional status. Muscle extraction was made for isoenzyme and alfa-GPD enzymatic studies. At the end of this period the same number of insects that did not fly, "bad" flyers (bf), were used as control and submitted to the same analysis. No isoenzyme difference was observed between gf and bf for the two populations. Main external factors influencing flight activity were w/l (PM1 P=0.0027; PM2 P=0.0209) and tp (PM1 P=0.0814; PM2 P=0.0118). However, PM1 and PM2 strongly differed with respect to alfa-GPD activity : it was the main difference found between PM1-gf and PM1-bf (P=0.0001), whereas it did not present any evidence for heterogeneity in PM2 (P=0.5995). We used two multivariate approaches to verify the differences between gf and bf (logistic regression and canonical variate analysis, CVA). Logistic regression was able to separate "good" from "bad" flyers of the old established laboratory strain (PM1) using as the unique parameter value the alfa-GPD activity (87 to 93% of correct attribution), while it reached lower scores (78 to 86%) in PM2, needing the combination of two or more parameters excluding alfa-GPD activity. (Résumé d'auteur)