Parasitological and immunological evaluation of a novel chemotherapeutic agent against visceral leishmaniasis

• Published in: Parasite immunology Vol. 42; no. 12; pp. e12784 - n/a
• Main Authors: Pereira, Isabela A. G., Mendonça, Débora V. C., Tavares, Grasiele S. V., Lage, Daniela P., Ramos, Fernanda F., Oliveira‐da‐Silva, João A., Antinarelli, Luciana M. R., Machado, Amanda S., Carvalho, Lívia M., Carvalho, Ana Maria R. S., Salustiano, Iorrana V., Reis, Thiago A. R., Bandeira, Raquel S., Silva, Alessandra M., Martins, Vívian T., Chávez‐Fumagalli, Miguel A., Humbert, Maria V., Roatt, Bruno M., Duarte, Mariana C., Menezes‐Souza, Daniel, Coimbra, Elaine S., Leite, João Paulo V., Coelho, Eduardo A. F., Gonçalves, Denise U.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-12-2020
• Subjects: Amastigotes; Amphotericin B; Animals; Antileishmanial agents; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; delivery systems; Female; Flavonoids; Flavonoids - administration & dosage; Flavonoids - chemistry; Flavonoids - pharmacology; immune response; Immune response (humoral); Immunity, Cellular - drug effects; Immunity, Humoral - drug effects; Immunosuppressive agents; Leishmania infantum - drug effects; Leishmania infantum - growth & development; Leishmania mexicana - drug effects; Leishmania mexicana - growth & development; leishmaniasis; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - immunology; Leishmaniasis, Visceral - parasitology; Lymphocytes T; Macrophages; Macrophages - drug effects; Macrophages - parasitology; Mice; Mice, Inbred BALB C; Micelles; Miltefosine; Minimum inhibitory concentration; Mitochondria; Parasite Load; Parasite resistance; Parasites; Parasitic diseases; Promastigotes; Toxicity; treatment; Visceral leishmaniasis; treatment; delivery systems; miltefosine; flavonoids; leishmaniasis; immune response
• ISSN: 0141-9838; 1365-3024
• DOI: 10.1111/pim.12784

Aims
Treatment for visceral leishmaniasis (VL) is hampered by the toxicity and/or high cost of drugs, as well as by emergence of parasite resistance. Therefore, there is an urgent need for new antileishmanial agents.
Methods and Results
In this study, the antileishmanial activity of a diprenylated flavonoid called 5,7,3,4’‐tetrahydroxy‐6,8‐diprenylisoflavone (CMt) was tested against Leishmania infantum and L amazonensis species. Results showed that CMt presented selectivity index (SI) of 70.0 and 165.0 against L infantum and L amazonensis promastigotes, respectively, and of 181.9 and 397.8 against respective axenic amastigotes. Amphotericin B (AmpB) showed lower SI values of 9.1 and 11.1 against L infantum and L amazonensis promastigotes, respectively, and of 12.5 and 14.3 against amastigotes, respectively. CMt was effective in the treatment of infected macrophages and caused alterations in the parasite mitochondria. L infantum‐infected mice treated with miltefosine, CMt alone or incorporated in polymeric micelles (CMt/Mic) presented significant reductions in the parasite load in distinct organs, when compared to the control groups. An antileishmanial Th1‐type cellular and humoral immune response were developed one and 15 days after treatment, with CMt/Mic‐treated mice presenting a better protective response.
Conclusion
Our data suggest that CMt/Mic could be evaluated as a chemotherapeutic agent against VL.
A diprenylated flavonoid called CMt showed a selective in vitro antileishmanial action against Leishmania infantum, and it was in vivo effective against murine visceral leishmaniasis.