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Cell death and ultrastructural alterations in Leishmania amazonensis caused by new compound 4-Nitrobenzaldehyde thiosemicarbazone derived from S-limonene.

ABSTRACT: The treatment of leishmaniasis with pentavalent antimonials is problematic because of their toxicity. Investigations of potentially active molecules are important to discover less toxic drugs that are viable economic alternatives for the treatment of leishmaniasis. Thiosemicarbazones are a group of molecules that are known for their wide versatility and biological activity. In the present study, we examined the antileishmania activity, mechanism of action, and biochemical alterations produced by a novel molecule, 4-nitrobenzaldehyde thiosemicarbazone (BZTS), derived from S-limonene against Leishmania amazonensis.BZTS inhibited the growth of the promastigote and axenic amastigote forms, with an IC50 of 3.8 and 8.0 ?M, respectively. Intracellular amastigotes were inhibited by the compound with an IC50 of 7.7 ?M. BZTS also had a CC50 of 88.8 ?M for the macrophage strain J774A1. BZTS altered the shape, size, and ultrastructure of the parasites, including damage to mitochondria, reflected by extensive swelling and disorganization of the inner mitochondrial membrane, intense cytoplasmic vacuolization, and the presence of concentric membrane structures inside the organelle. Cytoplasmic lipid bodies, vesicles inside vacuoles in the flagellar pocket, and enlargement were also observed. BZTS did not induce alterations in the plasma membrane or increase annexin-V fluorescence intensity, indicating no phosphatidylserine exposure. However, it induced the production of mitochondrial superoxide anion radicals.The present results indicate that BZTS induced dramatic effects on the ultrastructure of L. amazonensis, which might be associated with mitochondrial dysfunction and oxidative damage, leading to parasite death.

SUBMITTER: Britta EA

PROVIDER: S-EPMC4188478 | biostudies-other | 2014 Sep

REPOSITORIES: biostudies-other

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Cell death and ultrastructural alterations in Leishmania amazonensis caused by new compound 4-Nitrobenzaldehyde thiosemicarbazone derived from S-limonene.

Britta Elizandra Aparecida EA Scariot Débora Botura DB Falzirolli Hugo H Ueda-Nakamura Tânia T Silva Cleuza Conceição CC Filho Benedito Prado Dias BP Borsali Redouane R Nakamura Celso Vataru CV

BMC microbiology 20140926

<h4>Background</h4>The treatment of leishmaniasis with pentavalent antimonials is problematic because of their toxicity. Investigations of potentially active molecules are important to discover less toxic drugs that are viable economic alternatives for the treatment of leishmaniasis. Thiosemicarbazones are a group of molecules that are known for their wide versatility and biological activity. In the present study, we examined the antileishmania activity, mechanism of action, and biochemical alte ...[more]

PMID: 25253283

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Project description:Among neglected tropical diseases, leishmaniasis is one of the most important ones, affecting more than 12 million people worldwide. The available treatments are not well tolerated, and present diverse side effects, justifying the search for new therapeutic compounds. In the present study, the activity of ursolic acid (UA) and oleanolic acid (OA) were assayed in experimental cutaneous leishmaniasis (in vitro and in vivo). Promastigote forms of L. amazonensis were incubated with OA and UA for 24h, and effective concentration 50% (EC50) was estimated. Ultraestructural alterations in Leishmania amazonensis promastigotes after UA treatment were evaluated by transmission electron microscopy, and the possible mode of action was assayed through Annexin V and propidium iodide staining, caspase 3/7 activity, DNA fragmentation and transmembrane mitochondrial potential. The UA potential was evaluated in intracellular amastigotes, and its therapeutic potential was evaluated in L. amazonensis infected BALB/c mice. UA eliminated L. amazonensis promastigotes with an EC50 of 6.4 μg/mL, comparable with miltefosine, while OA presented only a marginal effect on promastigote forms at 100 μg/mL. The possible mechanism by which promastigotes were eliminated by UA was programmed cell death, independent of caspase 3/7, but it was highly dependent on mitochondria activity. UA was not toxic for peritoneal macrophages from BALB/c mice, and it was able to eliminate intracellular amastigotes, associated with nitric oxide (NO) production. OA did not eliminate amastigotes nor trigger NO. L. amazonensis infected BALB/c mice submitted to UA treatment presented lesser lesion size and parasitism compared to control. This study showed, for the first time, that UA eliminate promastigote forms through a mechanism associated with programed cell death, and importantly, was effective in vivo. Therefore, UA can be considered an interesting candidate for future tests as a prototype drug for the treatment of cutaneous leishmaniasis.

Dataset Information

Cell death and ultrastructural alterations in Leishmania amazonensis caused by new compound 4-Nitrobenzaldehyde thiosemicarbazone derived from S-limonene.

Publications

Cell death and ultrastructural alterations in Leishmania amazonensis caused by new compound 4-Nitrobenzaldehyde thiosemicarbazone derived from S-limonene.

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