ALECOMM

Leishmaniases are tropical neglected diseases endemic in 98 countries in the world, with about 380 million people exposed to the risk of infection by Leishmania parasite (WHO, 2018). This disease complex includes tegumentary leishmaniasis (TL), which is characterized by cutaneous, mucosal and cutaneous-diffuse forms of disease, and visceral leishmaniasis (VL) (Grimaldi and Tesh, 1993). TL is caused by distinct parasite species, such as Leishmania major, L. tropica, L. braziliensis, L. aethiopica, L. mexicana, among others; while VL is caused by L. donovani and L. infantum species (Alvar et al., 2012). Acute VL can cause anemia, fever, wasting, hepatosplenomegaly, immune suppression and it can be fatal if left untreated (Sundar and Singh, 2016).

Previous studies have shown that the protective response against infection relies on the induction of Th1-type immunity, characterized by the production of pro-inflammatory cytokines such as IFN-γ, IL-12, GM-CSF, among others, which stimulates infected host cells to kill parasites (Kedzierski and Evans 2014). On the contrary, a Th2-type immune response based on the production of cytokines such as IL-4, IL-5 and IL-10, contributes to disease progression by deactivation of parasitized macrophages (Dayakar et al., 2019).

VL treatment has long relied on the use of pentavalent antimonials. Despite antimonials have been reported to be effective against parasites, they are also toxic to the patients who can develop myalgia, arthralgia, anorexia and fever, as well as renal, cardiac and hepatic toxicity (Jain and Jain, 2013; Sundar and Singh, 2018). Amphotericin B (AmpB) has been used as a second line drug. It was originally developed as an antifungal agent but its antileishmanial activity was also demonstrated against distinct Leishmania species (Zauli-Nascimento et al., 2010; Corral et al., 2014; Mesquita et al., 2014). As with antimonials, however, treatment with AmpB is mainly related to renal and cardiac alterations, hemolysis and liver damage (Ortega et al., 2017). AmpB-based liposomal formulations are instead less toxic but their high costs limit their broad use as prophylactic drugs against VL (Sundar et al., 2019).

Miltefosine was originally described as an anti-tumor drug and later as an antileishmanial agent against parasite species causing VL (Mbui et al., 2019; Pijpers et al., 2019). Miltefosine presents a selective activity against parasites (Sane et al., 2010; Neira et al., 2019) by inhibiting the biosynthesis of the glycosylphosphatidylinositol receptor, which is a key molecule for Leishmania intracellular survival (Zhang et al., 2018). However, it causes teratogenicity and parasite resistance has been reported (Sundar and Singh, 2018). Therefore, the search to identify novel, effective and low-cost antileishmanial agents continues till date.

Previous studies have highlighted the relevance of drug repositioning for treatment against leishmaniasis. Rub et al. (2019) evaluated glyburide, an effective sugar lowering drug used for treatment of diabetes, regarding its antileishmanial activity against L. donovani. Results showed that glyburide inhibited parasite viability, suggesting its potential use as a drug to treat VL. In a similar fashion, hydroxyurea, an anti-tumor agent which is used for treatment of myeloid leukemia and melanoma, was also evaluated as an antiparasitic agent against L. mexicana species. In that study, the authors demonstrated that the drug caused alterations in the parasite cell cycle and effectively reduced infection of macrophages after treatment by its antileishmanial effect against intracellular amastigotes (Martinez-Rojano et al., 2008). Cisplatin, another anti-tumor agent, was evaluated against L. donovani and was proved to cause an increase in the levels of thiols and reactive oxygen species in the parasite, ultimately leading to Leishmania death (Kaur et al., 2010).

In the present study, Ivermectin (IVE) was tested in vitro and in vivo against L. infantum. IVE is a broad-spectrum antiparasitic agent commonly used for treatment of lice infestation, onchocerciasis, strongyloidiasis, scabies and cutaneous larva migrans (Omondi et al., 2018; Repetto et al., 2018). Here, IVE was evaluated in its free format or incorporated into a Poloxamer 407 (Pluronic® F127)-based polymeric micelle system (IVE/Mic) to treat L. infantum-infected BALB/c mice. Parasitological analyses by estimation of parasite load in spleen, liver, bone marrow (BM) and draining lymph nodes (dLN), as well as immunological assays, based on the evaluations of cellular and humoral responses, were performed after euthanasia of infected mice, one and 15 days post-therapy.