Please use this identifier to cite or link to this item: http://www.arca.fiocruz.br/handle/icict/17839
Title: Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi bloodstream trypomastigotes
Authors: Fonseca-Berzal, Cristina
Silva, Cristiane França
Menna-Barreto, Rubem F. S.
Batista, Marcos Meuser
Escario, José A.
Arán, Vicente J.
Gómez-Barrio, Alicia
Soeiro, Maria de Nazaré C.
Affilliation: CEI Campus Moncloa. UCM-UPM & CSIC. Madrid, Spain / Universidad Complutense de Madrid. Facultad de Farmacia. Departamento de Parasitología. Madrid, Spain.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
CEI Campus Moncloa. UCM-UPM & CSIC. Madrid, Spain / Universidad Complutense de Madrid. Facultad de Farmacia. Departamento de Parasitología. Madrid, Spain.
CEI Campus Moncloa. UCM-UPM & CSIC. Madrid, Spain / Consejo Superior de Investigaciones Científicas (CSIC). Instituto de Química Médica (IQM). Madrid, Spain.
CEI Campus Moncloa. UCM-UPM & CSIC. Madrid, Spain / Universidad Complutense de Madrid. Facultad de Farmacia. Departamento de Parasitología. Madrid, Spain.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Abstract: The phenotypic activity of two 5-nitroindazolinones, i.e. 2-benzyl-1-propyl (22) and 2-benzyl-1-butyl (24) derivatives, previously proposed as anti-Trypanosoma cruzi prototypes, was presently assayed on bloodstream trypomastigotes (BT) of the moderately drug-resistant Y strain. Further exploration of putative targets and cellular mechanisms involved in their activity was also carried out. Therefore, transmission electron microscopy, high-resolution respirometry and flow cytometry procedures were performed on BT treated for up to 24 h with the respective EC50 value of each derivative. Results demonstrated that although 22 and 24 were not as active as benznidazole in this in vitro assay on BT, both compounds triggered important damages in T. cruzi that lead to the parasite death. Ultrastructural alterations included shedding events, detachment of plasma membrane and nuclear envelope, loss of mitochondrial integrity, besides the occurrence of a large number of intracellular vesicles and profiles of endoplasmic reticulum surrounding cytoplasmic organelles such as mitochondrion. Moreover, both derivatives affected mitochondrion leading to this organelle dysfunction, as reflected by the inhibition in oxygen consumption and the loss of mitochondrial membrane potential. Altogether, the findings exposed in the present study propose autophagic processes and mitochondrial machinery as part of the mode of action of both 5-nitroindazolinones 22 and 24 on T. cruzi trypomastigotes.
Keywords: Chagas disease
autophagy
low cytometry
high-resolution respirometry
mitochondrion
transmission electron microscopy
keywords: Microscopia eletrônica de transmissão
Doença de Chagas
Autofagia
Citometria de fluxo
Respiração alta resolução
Mitocôndria
Issue Date: 2016
Publisher: Cambridge University Press
Citation: FONSECA-BERZAL, Cristina; et al. Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi bloodstream trypomastigotes. Parasitology, v.143, n.11, p.1469–1478, Sept. 2016.
DOI: 10.1017/S0031182016001098
ISSN: 0031-1820
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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