Abstract
Treatment of leishmaniasis is a challenging subject. Although available, chemotherapy is limited, presenting toxicity and adverse effects. New drugs with antileishmanial activity are being investigated, such as antiparasitic compounds derived from plants. In this work, we investigated the antileishmanial activity of the biflavonoid amentoflavone on the protozoan Leishmania amazonensis. Although the antileishmanial activity of amentoflavone has already been reported in vitro, the mechanisms involved in the parasite death, as well as its action in vivo, remain unknown. Amentoflavone demonstrated activity on intracellular amastigotes in macrophages obtained from BALB/c mice (IC50 2.3 ± 0.93 μM). No cytotoxicity was observed and the selectivity index was estimated as greater than 10. Using BALB/c mice infected with L. amazonensis we verified the effect of an intralesional treatment with amentoflavone (0.05 mg/kg/dose, in a total of 5 doses every 4 days). Parasite quantification demonstrated that amentoflavone reduced the parasite load in treated footpads (46.3% reduction by limiting dilution assay and 56.5% reduction by Real Time Polymerase Chain Reaction). Amentoflavone decreased the nitric oxide production in peritoneal macrophages obtained from treated animals. The treatment also increased the expression of ferritin and decreased iNOS expression at the site of infection. Furthemore, it increased the production of ROS in peritoneal macrophages infected in vitro. The increase of ROS in vitro, associated with the reduction of NO and iNOS expression in vivo, points to the antioxidant/prooxidant potential of amentoflavone, which may play an important role in the balance between inflammatory and anti-inflammatory patterns at the infection site. Taken together these results suggest that amentoflavone has the potential to be used in the treatment of cutaneous leishmaniasis, working as an ally in the control and development of the lesion.
Highlights
Leishmaniases are a complex of infectious diseases caused by several species of protozoa from the genus Leishmania, which are transmitted between vertebrate and invertebrate hosts by the bite of infected female sandflies
Intralesional treatment with amentoflavone did not show hepatic or renal toxicity since no alterations were observed in the biochemical markers alanine transaminase (ALT), aspartate transaminase (AST) and creatinine
Weniger and collaborators (Weniger et al, 2006) found no activity against L. donovani axenic amastigotes, but our group have shown that amentoflavone can disrupt the membrane potential of mitochondria and effectively kill L. amazonensis promastigotes
Summary
Leishmaniases are a complex of infectious diseases caused by several species of protozoa from the genus Leishmania, which are transmitted between vertebrate and invertebrate hosts by the bite of infected female sandflies. In 2010, the World Health Organization (WHO) promoted the use of local therapies to treat cases of uncomplicated CL (World Health Organization, 2010) and the intralesional approach was included in the CL treatment recommendations in Brazil (Brasil, 2017), after studies in the country that had already shown the benefits of CL local treatment (Oliveira-Neto et al, 1997; de Oliveira Duque et al, 2016) These studies highlighted the decrease in adverse effects and toxicity, and the cost and accessibility of treatment, especially in rural areas (Añez et al, 2018; Arboleda et al, 2019; de Oliveira Duque et al, 2019). Intralesional treatment can offer advantages such as simplicity, efficiency, and safety, especially when the patient conditions do not allow systemic chemotherapy (de Oliveira Duque et al, 2019)
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