Oxidative stress induced in Leishmania infatum by batzelladine L and norbatzelladine L alkaloids isolated from the marine sponge Monanchora arbuscula[manuell

Abstract

Leishmaniasis and American Trypanosomiais are protozoan neglected diseases affecting about 12 and 28 million people yearly in developing countries, respectively, with few and toxic alternatives for treatment. The study of new cell death pathways in protozoan parasites is an important strategy to control the progress of infectious diseases. In the search towards new drug leads to treat parasitic infectious diseases, marine natural products are considered promising tools for the discovery of drug prototypes. In the present investigation, the alkaloids batzelladine L and norbatzelladine L, isolated from the marine sponge Monanchora arbuscula, were tested against Leishmania infantum and T. cruzi parasites. Both alkaloids displayed IC50 in the range between 1 to 4 µg/mL, with an IC50 against a mammalian cell in the range between of 13 to 44 µg/mL. Batzelladine L and norbatzelladine L altered the permeability of Leishmania plasma membrane, but norbatzelladine L induced a time-dependent and the highest penetration of the fluorescent dye SYTOX Green. Both batzelladine L and norbatzelladine L induced rapid depolarization of Leishmania mitochondrial membrane potential, resulting in an up-regulation of reactive oxygen species (ROS), leading to oxidative stress. Moreover, batzelladine L demonstrated the highest capacity to induce ROS production, in a 4,300-fold higher levels when compared to untreated parasites. Flow cytometry analysis demonstrated an intense exposure of phospatidylserine in the outer leaflet of plasma membrane of batzelladine L-treated parasites. The size of the side alkyl chain of the two guanidine alkaloids batzelladine L and norbatzelladine L seems to play a major role in the antiparasitic effect. Both alkaloids represent promising tools to study novel cellular death pathways in Leishmania parasites.