Amentoflavone isolated from Selaginella sellowii Hieron induces mitochondrial dysfunction in Leishmania amazonensis promastigotes

Leishmaniasis chemotherapy is a bottleneck in disease treatment. Although available, chemotherapy is limited, toxic, painful, and does not lead to parasite clearance, with parasite resistance also being reported. Therefore, new therapeutic options are being investigated, such as plant-derived anti-p...

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Published in:	Parasitology international Vol. 86; p. 102458
Main Authors:	Rizk, Yasmin Silva, Hardoim, Daiana de Jesus, Santos, Kaique Bertrand Almeida, Zaverucha-do-Valle, Tânia, Taniwaki, Noemi Nosomi, Almeida-Souza, Fernando, Carollo, Carlos Alexandre, Vannier-Santos, Marcos André, Arruda, Carla Cardozo Pinto de, Calabrese, Kátia da Silva
Format:	Journal Article
Language:	English
Published:	Elsevier B.V 01-02-2022
Subjects:	ADME Antileishmanial activity Biflavonoid Cell death Electron microscopy Mitochondria Biflavonoid Mitochondria Electron microscopy Cell death ADME Antileishmanial activity
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Summary:	Leishmaniasis chemotherapy is a bottleneck in disease treatment. Although available, chemotherapy is limited, toxic, painful, and does not lead to parasite clearance, with parasite resistance also being reported. Therefore, new therapeutic options are being investigated, such as plant-derived anti-parasitic compounds. Amentoflavone is the most common biflavonoid in the Selaginella genus, and its antileishmanial activity has already been described on Leishmania amazonensis intracellular amastigotes but its direct action on the parasite is controversial. In this work we demonstrate that amentoflavone is active on L. amazonensis promastigotes (IC50 = 28.5 ± 2.0 μM) and amastigotes. Transmission electron microscopy of amentoflavone-treated promastigotes showed myelin-like figures, autophagosomes as well as enlarged mitochondria. Treated parasites also presented multiple lipid droplets and altered basal body organization. Similarly, intracellular amastigotes presented swollen mitochondria, membrane fragments in the lumen of the flagellar pocket as well as autophagic vacuoles. Flow cytometric analysis after TMRE staining showed that amentoflavone strongly decreased mitochondrial membrane potential. In silico analysis shows that amentoflavone physic-chemical, drug-likeness and bioavailability characteristics suggest it might be suitable for oral administration. We concluded that amentoflavone presents a direct effect on L. amazonensis parasites, causing mitochondrial dysfunction and parasite killing. Therefore, all results point for the potential of amentoflavone as a promising candidate for conducting advanced studies for the development of drugs against leishmaniasis. [Display omitted] •Amentoflavone can kill Leishmania amazonensis promastigotes, with IC50 of 28.5 ± 2.0 μM;•Amentoflavone induces mitochondria swelling, autolysosome and lipid drops in parasite;•Amentoflavone alters mitochondrial membrane potential in L. amazonensis promastigote;•Amentoflavone in silico analysis suggets it might be suitable for oral administration.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1383-5769 1873-0329
DOI:	10.1016/j.parint.2021.102458