Exploring drug repositioning for leishmaniasis treatment: Ivermectin plus polymeric micelles induce immunological response and protection against tegumentary leishmaniasis

by Selleckchem | Mar 01 2023

Leishmania amazonensis can cause a wide spectrum of the clinical manifestations of leishmaniasis in humans. The development of new therapeutics is a long and expensive task; in this context, drug repositioning could be considered a strategy to identify new biological actions of known products. In the present study, ivermectin (IVE) was tested against distinct Leishmania species able to cause disease in humans. In vitro experiments showed that IVE was effective to reduce the infection degree and parasite load in Leishmania donovani- and L. amazonensis-infected macrophages that were treated with it. In addition, using the culture supernatant of treated macrophages, higher production of IFN-γ and IL-12 and lower levels of IL-4 and IL-10 were found. Then, IVE was used in a pure form or incorporated into Poloxamer 407-based polymeric micelles (IVE/M) for the treatment of L. amazonensis-infected BALB/c mice. Animals (n = 16 per group) were infected and later received saline, empty micelles, amphotericin B (AmpB), IVE, or IVE/M. They were euthanized at one (n = 8 per group) and 30 (n = 8 per group) days after treatment and, in both endpoints, immunological, parasitological, and biochemical evaluations were performed. Results showed that both IVE and IVE/M induced higher levels of IFN-γ, IL-12, GM-CSF, nitrite, and IgG2a antibodies, as well as higher IFN-γ expression evaluated by RT-qPCR in spleen cell cultures. Such animals showed low organic toxicity, as well as significant reductions in the lesion's average diameter and parasite load in their infected tissue, spleen, liver, and draining lymph node. The efficacy was maintained 30 days post-therapy, while control mice developed a polarized Th2-type response and high parasite load. In this context, IVE could be considered as a new candidate to be applied in future studies for the treatment against distinct Leishmania species.

Comments：

This study evaluated the effectiveness of ivermectin (IVE) against two species of Leishmania, which are parasites that can cause leishmaniasis in humans. In vitro experiments showed that IVE was able to reduce the infection and parasite load in Leishmania-infected macrophages, and also induced the production of pro-inflammatory cytokines (IFN-γ and IL-12) and reduced the levels of anti-inflammatory cytokines (IL-4 and IL-10).

Additionally, IVE was also tested in infected mice in both its pure form and incorporated into polymeric micelles (IVE/M). The results showed that both IVE and IVE/M treatments induced higher levels of pro-inflammatory cytokines and antibodies, as well as reducing the parasite load and lesion size in infected tissues. Furthermore, the efficacy of the treatment was maintained 30 days after therapy, while control mice developed a more anti-inflammatory response and higher parasite load.

Overall, the results of this study suggest that IVE has the potential to be a candidate for the treatment of leishmaniasis caused by different species of Leishmania. Further studies are necessary to fully evaluate its safety and efficacy.