Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum
| Autor: | Andre G. Tempone, Carlos Alberto Pereira Tavares, Simone Odília Antunes Fernandes, Miguel A. Chávez-Fumagalli, Juliana T. Mesquita, Valbert Nascimento Cardoso, Manuel Soto, João Paulo Viana Leite, Eduardo A.F. Coelho, Laís M. Mata, Paula S. Lage |
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| Přispěvatelé: | Sao Paulo Research Foundation, Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (Brasil) |
| Rok vydání: | 2015 |
| Předmět: |
Biodistribution
Cell Membrane Permeability Antiprotozoal Agents Drug Evaluation Preclinical Spleen Biology Strychnos Leishmania spp Mice medicine Animals Humans Tissue Distribution Leishmania infantum Amastigote Flavonoids Ex vivo biodistribution Mice Inbred BALB C General Veterinary Plant Extracts General Medicine Antileishmanial activity biology.organism_classification medicine.disease Molecular biology In vitro Mitochondria Scintigraphic images Treatment Infectious Diseases medicine.anatomical_structure Visceral leishmaniasis Mechanism of action Biochemistry Insect Science Strychnobiflavone Leishmaniasis Visceral Female Parasitology Mitochondrial membrane potential medicine.symptom Reactive Oxygen Species Ex vivo |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname LOCUS Repositório Institucional da UFV Universidade Federal de Viçosa (UFV) instacron:UFV |
| Popis: | © 2015, Springer-Verlag Berlin Heidelberg. 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. This work was supported by grants from Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica (INCT-Nanobiofar), FAPEMIG (CBB-APQ-00819-12), CNPq (APQ-472090/2011-9, APQ- 482976/2012-8, and APQ-488237/2013-0) and São Paulo State Research Fundation (FAPESP 2012/18756-1). MACF is a grant recipient of FAPEMIG/CAPES. EAFC, VNC and AGT are grant recipient of CNPq |
| Databáze: | OpenAIRE |
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