Estudos pré-clínicos de complexos metálicos a base de prata contra Leishmania spp. (Kinetoplastida: Trypanosomatidae)

Abstract

Leishmaniasis is a disease caused by parasites of the genus Leishmania, transmitted by the bite of an infected female sandfly. Human infections can manifest in different ways, such as Cutaneous Leishmaniasis (CL) and Visceral Leishmaniasis (VL). Treatment is by pentavalent antimonials that, despite their effectiveness, have side effects and routes of administration that require hospitalization and clinical follow-up by professionals. Medicinal Inorganic Chemistry offers research possibilities, and metal have advantages over existing drugs, among which silver and its ions stand out for their reported diversity of antimicrobial activity and low citotoxicity. The objective of this work was to study the citotoxic activity, the in vitro effect of metallic complexes based on silver (Ag1 and Ag2) against the promastigote and amastigote forms of Leishmania Leishmania) amazonensis and L. (Viannia) guyanensis, and evaluate the activity of two gels, one containing the Ag1 complex and the other containing the Ag2 complex incorporated, in the treatment of lesions caused by these species in experimental animals - golden hamsters (Mesocricetus auratus). The complexes were synthesized by the ICMATE team, Padua – Itália and sent for biological tests at INPA. The complexes were evaluated in vitro against promastigote and amastigote forms of Leishmania sp., the latter internalized in primary cultures - murine peritoneal macrophages and human monocytes. The cytotoxic activity of the complexes to these cells was performed by colorimetric method, with Alamar Blue® reagent. For in vivo tests, base gels were prepared and metal complexes were incorporated. The animals were infected with Leishmania sp. After appearance of the lesions, the topical treatment was started for 30 consecutive days, with the formulated gels. Against promastigote forms of L. (L.) amazonensis, both complexes showed a reduction in the number of viable parasites, mainly for the Ag2 complex (IC50 <10), whereas against amastigote forms, the Ag1 complex showed a greater reduction in infected macrophages and monocytes (IC50 6.09 and 23.28, respectively). Against the species L. (V.) guyanensis, the Ag2 complex showed anti-Leishmania activity in amastigote internalized in macrophages, with reduction in infected cells. In cytotoxic teste, the Ag2 complex did not show cytotoxicity for both cell type. The Ag2 complex showed the most tolerable selectivity index (IS) among all when evaluated in peritoneal macrophages. As for topical treatment, the best result was using the Ag2 complex in infection caused by L. (L.) amazonensis, with a reduction in the volume of the lesion after the 14th day of treatment, which also showed a lower parasitic load in parasite culture. Based on these results, it is possible to infer anti-Leishmania activity by silver complexes, taking into account that such activity is related to the species, evolutionary forms of the parasite and time treatment.