In vitro and in vivo activity of a palladacycle complex on Leishmania (Leishmania) amazonensis

• Published in: PLoS neglected tropical diseases 2012-05, Vol.6 (5), p.e1626
• Main Authors: Paladi, Carolina de Siqueira, Pimentel, Isabella Aparecida Salerno, Katz, Simone, Cunha, Rodrigo L O R, Judice, Wagner Alves de Souza, Caires, Antonio C F, Barbiéri, Clara Lúcia
• Format: Article
• Language: English
• Subjects: Animals; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - pharmacology; Biology; Bone marrow; Brazil; Care and treatment; Cricetinae; Cysteine; Diagnosis; Disease Models, Animal; Female; Fluorometry - methods; Humans; Injections, Subcutaneous; Laboratory tests; Leishmania mexicana - drug effects; Leishmania mexicana - isolation & purification; Leishmaniasis; Leishmaniasis, Cutaneous - drug therapy; Leishmaniasis, Cutaneous - parasitology; Leishmaniasis, Cutaneous - pathology; Lesions; Macrophages; Macrophages - drug effects; Mesocricetus; Mice; Mice, Inbred BALB C; Organometallic Compounds - administration & dosage; Organometallic Compounds - pharmacology; Parasites; Parasitic diseases; Parasitic Sensitivity Tests; Properties; Protozoa; Toxicity; Treatment Outcome; Tropical diseases; Vector-borne diseases
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0001626

Antitumor cyclopalladated complexes with low toxicity to laboratory animals have shown leishmanicidal effect. These findings stimulated us to test the leishmanicidal property of one palladacycle compound called DPPE 1.2 on Leishmania (Leishmania) amazonensis, an agent of simple and diffuse forms of cutaneous leishmaniasis in the Amazon region, Brazil. Promastigotes of L. (L.) amazonensis and infected bone marrow-derived macrophages were treated with different concentrations of DPPE 1.2. In in vivo assays foot lesions of L. (L.) amazonensis-infected BALB/c mice were injected subcutaneously with DPPE 1.2 and control animals received either Glucantime or PBS. The effect of DPPE 1.2 on cathepsin B activity of L. (L.) amazonensis amastigotes was assayed spectrofluorometrically by use of fluorogenic substrates. The main findings were: 1) axenic L. (L.) amazonensis promastigotes were destroyed by nanomolar concentrations of DPPE 1.2 (IC50 = 2.13 nM); 2) intracellular parasites were killed by DPPE 1.2 (IC50 = 128.35 nM), and the drug displayed 10-fold less toxicity to macrophages (CC50 = 1,267 nM); 3) one month after intralesional injection of DPPE 1.2 infected BALB/c mice showed a significant decrease of foot lesion size and a reduction of 97% of parasite burdens when compared to controls that received PBS; 4) DPPE 1.2 inhibited the cysteine protease activity of L. (L.) amazonensis amastigotes and more significantly the cathepsin B activity. The present results demonstrated that DPPE 1.2 can destroy L. (L.) amazonensis in vitro and in vivo at concentrations that are non toxic to the host. We believe these findings support the potential use of DPPE 1.2 as an alternative choice for the chemotherapy of leishmaniasis.