Abstract
The currently available treatments for Chagas disease show limited therapeutic potential and are associated with serious side effects. Attempting to find alternative drugs isolated from Nature as agents against Trypanosoma cruzi has been our goal. Recently, we have demonstrated the in vitro anti-T. cruzi activities of two secondary metabolites isolated from the hydro-ethanolic extract of the aerial parts of Aristeguietia glutinosa (Lam.), (family Asteraceae). These active principles displayed poor hemolytic activity, low toxicity against murine macrophages, and absence of mutagenicity. Herein, proof of concept in vivo studies of the whole hydro-ethanolic extract of the aerial parts of Aristeguietia glutinosa and of the most active component isolated from the hydro-ethanolic extract, i.e., (+)-15-hydroxy-7-labden-17-al, was done in a murine acute model of Chagas disease. Both treatments caused a decrease in the animals’ parasitemia. Metabolomic mechanism of action studies were done by 1H-NMR, both on the extract and on the active compounds, examining the effects of the metabolites both on membrane sterol biosynthesis and mitochondrial dehydrogenases, whereby we found that one of the metabolites inhibited the activity of the parasite mitochondrial dehydrogenases and the other inhibited the biosynthesis of parasite membrane sterols. The results are interesting in the context of popular use of plants for the treatment of Chagas disease.
Highlights
Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi)
The present study was conducted in order to prove the concept, for in vivo anti-T. cruzi evaluation of active principles and the whole plant extract from Aristeguietia glutinosa and to attempt to elucidate the possible mechanism(s) of action
We studied the effects of the WHEAP and isolated compounds from the different fractions against the bloodstream trypomastigote form of T. cruzi at 250 μg/mL and at 4 °C (Table 1) [17]
Summary
Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi). It is transmitted to humans by bites and concomitant defecation of different triatomine species, which carry the parasite in their contaminated feces. Activity against epimastigotes (IC50 = 19.6 μg/mL), whereas the isolated compounds (+)-15-hydroxy-7labden-17-al (1, Figure 1) and (+)-13,14,15,16-tetranorlabd-7-en-l7,12-olide (2, Figure 1) were nearly seven- and one a half-fold, respectively (IC50 = 3.0 and 15.6 μg/mL or 9.8 and 62.9 μM), more active than the original extract while showing both a lack of mammalian cytotoxic and mutagenic effects, whereas the clinically used nifurtimox (Nfx, IC50 = 7.7 μM [16]), equipotent to compound 1, is mutagenic [16] This could at least support the vernacular medicinal use of A. glutinosa Lam. as an anti-Chagas agent. The present study was conducted in order to prove the concept, for in vivo anti-T. cruzi evaluation of active principles and the whole plant extract from Aristeguietia glutinosa and to attempt to elucidate the possible mechanism(s) of action
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