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Abstract
Previous results demonstrate that the hybrid synthetic pterocarpanquinone LQB-118 presents antileishmanial activity against Leishmania amazonensis in a mouse model. The aim of the present study was to use a hamster model to investigate whether LQB-118 presents antileishmanial activity against Leishmania (Viannia) braziliensis, which is the major Leishmania species related to American tegumentary leishmaniasis. The in vitro antileishmanial activity of LQB-118 on L. braziliensis was tested on the promastigote and intracellular amastigote forms. The cell death induced by LQB-118 in the L. braziliensis promastigotes was analyzed using an annexin V-FITC/PI kit, the oxidative stress was evaluated by 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) and the ATP content by luminescence. In situ labeling of DNA fragments by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis in the intracellular amastigotes. L. braziliensis-infected hamsters were treated from the seventh day of infection with LQB-118 administered intralesionally (26 µg/kg/day, three times a week) or orally (4,3 mg/kg/day, five times a week) for eight weeks. LQB-118 was active against the L. braziliensis promastigotes and intracellular amastigotes, producing IC50 (50% inhibitory concentration) values of 3,4±0,1 and 7,5±0,8 µM, respectively. LQB-118 induced promastigote phosphatidylserine externalization accompanied by increased reactive oxygen species production and ATP depletion. Intracellular amastigote DNA fragmentation was also observed, without affecting the viability of macrophages. The treatment of L. braziliensis-infected hamsters with LQB-118, either orally or intralesionally, was effective in the control of lesion size, parasite load and increase intradermal reaction to parasite antigen. Taken together, these results show that the antileishmanial effect of LQB-118 extends to L. braziliensis in the hamster model, involves the induction of parasite apoptosis and shows promising therapeutic option by oral or local routes in leishmaniasis.
Highlights
Leishmaniases are neglected diseases that occur in 98 countries and show an annual incidence of 1 to 1.5 million people worldwide [1,2,3]
In vitro antileishmanial activity against L. braziliensis To evaluate whether the previously demonstrated antileishmanial activity of LQB-118 on L. amazonensis occurred on L. braziliensis, promastigotes were initially cultivated in the presence of different concentrations of LQB-118 (0–20 mM) for 3 days
To investigate whether the antileishmanial effect of LQB-118 observed in the promastigote forms extended to the intracellular amastigote, infected hamster macrophages were treated with different LQB-118 concentrations (0–20 mM) for 48 h
Summary
Leishmaniases are neglected diseases that occur in 98 countries and show an annual incidence of 1 to 1.5 million people worldwide [1,2,3]. American tegumentary leishmaniasis (ATL) presents with a spectrum of clinical forms, including cutaneous, mucosal and disseminated and diffuse cutaneous leishmaniasis. Leishmania (Viannia) braziliensis is the important species that causes ATL and is the major agent for the mucosal forms in Brazil [4,5]. The treatment of leishmaniasis is restricted to a few extremely toxic drugs, quite costly and increasingly challenged by the development of parasite resistance to drugs [6,7]. Because of high cost or limited effectiveness, the supply of the new formulations of amphotericin B and oral miltefosine have been insufficient to meet the demand, especially in endemic regions [8,9,10]. The development of drugs that are less toxic, more effective, less costly and orally administrable is critical for the treatment of leishmaniasis in endemic countries [10]
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