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BACKGROUND  Leishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because translocator protein (TSPO) levels are reduced in  Leishmania amazonensis -infected cells and because this protein participates in apoptosis and immunomodulation, TSPO represents a potential target for  Leishmania  chemotherapy. The present study evaluated PK11195, a ligand of this protein, as an anti-leishmanial agent.    OBJECTIVE  To evaluate the leishmanicidal activity of PK11195 against  L. amazonensis  in infected CBA mouse macrophages  in vitro .    METHODS  The viability of axenic  L. amazonensis ,  Leishmania major , and  Leishmania braziliensis  promastigotes was assessed after 48 h treatment with PK11195 (0.2-400 µM). Additionally, intracellular parasite viability was evaluated to determine IC 50  values and the number of viable parasites in infected macrophages treated with PK11195 (50-100 µM). Infected macrophages were then treated with PK11195 (25-100 µM) to determine the percentage of  L. amazonensis -infected cells and the number of parasites per infected cell. Electron microscopy was used to investigate morphological changes caused by PK11195. The production of free oxygen radicals, nitric oxide, and pro-inflammatory cytokines was also evaluated in infected macrophages treated with PK11195 and primed or not primed with IFN-γ.    FINDINGS  Median IC 50  values for PK11195 were 14.2 µM for  L. amazonensis , 8.2 µM for  L. major , and 3.5 µM for  L. braziliensis . The selective index value for  L. amazonensis  was 13.7, indicating the safety of PK11195 for future testing in mammals. Time- and dose-dependent reductions in the percentage of infected macrophages, the number of parasites per infected macrophage, and the number of viable intracellular parasites were observed. Electron microscopy revealed some morphological alterations suggestive of autophagy. Interestingly, MCP-1 and superoxide levels were reduced in  L. amazonensis -infected macrophages treated with PK11195.    MAIN CONCLUSIONS  PK11195 causes the killing of amastigotes  in vitro  by mechanisms independent of inflammatory mediators and causes morphological alterations within  Leishmania  parasites, suggestive of autophagy, at doses that are non-toxic to macrophages. Thus, this molecule has demonstrated potential as an anti-leishmanial agent.

In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195