Abstract
The present study focused on the activity of the palladacycle complex DPPE 1.1 on Leishmania (Leishmania) amazonensis. Promastigotes of L. (L.) amazonensis were destroyed in vitro by nanomolar concentrations of DPPE 1.1, whereas intracellular amastigotes were killed at drug concentrations fivefold less toxic than those harmful to macrophages. L. (L.) amazonensis-infected BALB/c mice were treated by intralesional injection of DPPE 1.1. Animals treated with 3.5 and 7.0 mg/kg of DPPE 1.1 showed a significant decrease of foot lesion sizes and a parasite load reduction of 93 and 99%, respectively, when compared to untreated controls. Furthermore, DPPE 1.1 was non-toxic to treated animals. The cathepsin B activity of L. (L.) amazonensis amastigotes was inhibited by DPPE 1.1 as demonstrated spectrofluorometrically by use of a specific fluorogenic substrate. Analysis of T-cells populations in mice treated with DPPE 1.1 and untreated controls was performed by fluorescence-activated cell sorter (FACS). IFN-γ was measured in supernatants of lymphocytes from popliteal and inguinal lymph nodes isolated from treated and untreated mice and stimulated with L. (L.) amazonensis amastigotes extract and active TGF-β was evaluated in supernatants of foot lesions; both dosages were carried out by means of a double-sandwich ELISA assay. A significant increase of TCD4+ and TCD8+ lymphocytes and IFN-γ secretion was displayed in mice treated with DPPE 1.1 compared to untreated animals, whereas a significant reduction of active TGF-β was observed in treated mice. These findings open perspectives for further investment in DPPE 1.1 as an alternative option for the chemotherapy of cutaneous leishmaniasis.
Highlights
Leishmaniasis comprise a group of parasitic diseases displaying a wide clinical spectrum ranging from cutaneous, mucocutaneous, and visceral leishmaniasis
The present study shows the action of the palladacycle complex DPPE 1.1 on promastigotes, intracellular amastigotes, and cutaneous lesions in BALB/c mice infected with L. (L.) amazonensis
A growth curve similar to control was observed when L. (L.) amazonensis promastigotes were cultured in the presence of the highest concentration of DMSO used for DPPE 1.1 solubilization (0.04%)
Summary
Leishmaniasis comprise a group of parasitic diseases displaying a wide clinical spectrum ranging from cutaneous, mucocutaneous, and visceral leishmaniasis. Other alternatives for treatment of leishmaniasis are miltefosine, paromomycin, and sitamaquine These compounds have shown efficacy against cutaneous and visceral leishmaniasis they have restricted use due to host teratogenicity, development of parasite resistance and induction of undesirable adverse effects (Thakur et al, 2000; Sundar et al, 2002; Croft and Coombs, 2003; Soto et al, 2004; Jha et al, 2005). Several findings suggest that compounds that activate the host immune system enhance the efficacy of antileishmanial drugs (Gupta et al, 2011; Seifert et al, 2015). The effect of the palladacycle complex DPPE 1.2 on in vitro and in vivo L. The high efficacy of DPPE 1.1 on L. (L.) amazonensis infection in vivo is followed by the modulation of the host immune responses
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