CONICET | Buscador de Institutos y Recursos Humanos

tBackground: Chagas disease or American Trypanosomiasis is caused by the flagellated protozoan parasiteTrypanosoma cruzi (T. cruzi) and is recognized by the WHO as one of the world?s 17 neglected tropicaldiseases. Only two drugs (Benznidazol, Bz and Nifurtimox, Nx) are currently accepted for treatment,however they cause severe adverse effects and their efficacy is still controversial. It is then important toexplore for new drugs.Purpose: Programmed cell death (PCD) in parasites offers interesting new therapeutic targets. The aim ofthis work was to evaluate the induction of PCD in T. cruzi by two natural sesquiterpene lactones (STLs),dehydroleucodine (DhL) and helenalin (Hln) as compared with the two conventional drugs, Bz and Nx.Material and Methods: Hln and DhL were isolated from aerial parts of Gaillardia megapotamica andArtemisia douglassiana Besser, respectively. Purity of compounds (greater than 95%) was confirmed by13C-nuclear magnetic resonance, melting point analysis, and optical rotation. Induction of PCD in T. cruziepimastigotes and trypomastigotes by DhL, Hln, Bz and Nx was assayed by phosphatidylserine expo-sure at the parasite surface and by detection of DNA fragmentation using the TUNEL assay. Trypanocidalactivity of natural and synthetic compounds was assayed by measuring parasite viability using the MTTmethod.Results: The two natural STLs, DhL and Hln, induce programmed cell death in both, the replicative epi-mastigote form and the infective trypomastigote form of T. cruzi. Interestingly, the two conventionalantichagasic drugs (Bz and Nx) do not induce programmed cell death. A combination of DhL and eitherBz or Nx showed an increased effect of natural compounds and synthetic drugs on the decrease of parasiteviability.Conclusion: DhL and Hln induce programmed cell death in T. cruzi replicative epimastigote and infectivetrypomastigote forms, which is a different mechanism of action than the conventional drugs to kill theparasite. Therefore DhL and Hln may offer an interesting option for the treatment of Chagas disease, aloneor in combination with conventional drugs