Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum.
The present study aimed to investigate the in vitro antileishmanial activity of strychnobiflavone flavonoid against Leishmania infantum, as well as its mechanism of action, and evaluate the ex vivo biodistribution profile of the flavonoid in naive BALB/c mice. The antileishmanial activity (IC50 value) of strychnobiflavone against stationary promastigote and amastigote-like stages of the parasites was of 5.4 and 18.9 μM, respectively; with a 50% cytotoxic concentration (CC50) value of 125.0 μM on murine macrophages, resulting in selectivity index (SI) of 23.2 and 6.6, respectively. Amphotericin B, used as a positive control, presented SI values of 7.6 and 3.3 for promastigote and amastigote-like stages of L. infantum, respectively. The strychnobiflavone was also effective in reducing in significant levels the percentage of infected macrophages, as well as the number of amastigotes per macrophage, after the treatment of infected macrophages using the flavonoid. By using different fluorescent probes, we investigated the bioenergetics metabolism of L. infantum promastigotes and demonstrated that the flavonoid caused the depolarization of the mitochondrial membrane potential, without affecting the production of reactive oxygen species. In addition, using SYTOX(®) green as a fluorescent probe, the strychnobiflavone demonstrated no interference in plasma membrane permeability. For the ex vivo biodistribution assays, the flavonoid was labeled with technetium-(99m) and studied in a mouse model by intraperitoneal route. After a single dose administration, the scintigraphic images demonstrated a highest uptake by the liver and spleen of the animals within 60 min, resulting in low concentrations after 24 h. The present study therefore demonstrated, for the first time, the antileishmanial activity of the strychnobiflavone against L. infantum, and suggests that the mitochondria of the parasites may be the possible target organelle. The preferential distribution of this compound into the liver and spleen of the animals could warrant its employ in the treatment of visceral leishmaniasis.
Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Minas Gerais, Brazil.
Paula S
PS
Lage
Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Minas Gerais, Brazil.
Miguel A
MA
Chávez-Fumagalli
Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo, 01246-902, São Paulo, Brazil.
Juliana T
JT
Mesquita
Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
Laís M
LM
Mata
Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
Simone O A
SO
Fernandes
Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
Valbert N
VN
Cardoso
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049, Madrid, Spain.
Manuel
M
Soto
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
Carlos A P
CA
Tavares
Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, 36570-900, Minas Gerais, Brazil.
João P V
JP
Leite
Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo, 01246-902, São Paulo, Brazil.
Andre G
AG
Tempone
Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Minas Gerais, Brazil. eduardoferrazcoelho@yahoo.com.br.|Laboratório de Biotecnologia Aplicada ao Estudo das Leishmanioses, Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Belo Horizonte, 31270-901, Minas Gerais, Brazil. eduardoferrazcoelho@yahoo.com.br.
Eduardo A F
EA
Coelho
D000818:Animals; D000981:Antiprotozoal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000302:isolation & purification; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects* / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage* / Q000302:isolation & purification; D017382:Reactive Oxygen Species / Q000378:metabolism; D031451:Strychnos / Q000737:chemistry*; D014018:Tissue Distribution
D000981:Antiprotozoal Agents; D005419:Flavonoids; D010936:Plant Extracts; D017382:Reactive Oxygen Species
Antileishmanial activity; Ex vivo biodistribution; Leishmania spp.; Mitochondrial membrane potential; Scintigraphic images; Strychnobiflavone; Treatment