Abstract
Leishmaniases are neglected infectious diseases caused by parasites of the ‘protozoan’ genus Leishmania. Depending on the parasite species, different clinical forms are known as cutaneous, muco-cutaneous, and the visceral leishmaniasis (VL). VL is particularly fatal and the therapy presents limitations. In the search for new anti-leishmanial hit compounds, seven natural sesquiterpene lactones were evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum, a pathogen causing VL. The pseudoguaianolides mexicanin I and helenalin acetate demonstrated the highest selectivity and potency against intracellular amastigotes. In addition, promastigotes treated with helenalin acetate were subject to an ultrastructural and biochemical investigation. The lethal action of the compound was investigated by fluorescence-activated cell sorting and related techniques to detect alterations in reactive oxygen species (ROS) content, plasma membrane permeability, and mitochondrial membrane potential. Helenalin acetate significantly reduced the mitochondrial membrane potential and the mitochondrial structural damage was also confirmed by transmission electron microscopy, displaying an intense organelle swelling. No alteration of plasma membrane permeability or ROS content could be detected. Additionally, helenalin acetate significantly increased the production of nitric oxide in peritoneal macrophages, probably potentiating the activity against the intracellular amastigotes. Helenalin acetate could hence be a useful anti-leishmanial scaffold for further optimization studies.
Highlights
Leishmaniases are listed as neglected tropical diseases by the World Health Organization [1].Nowadays, these diseases affect 98 countries
We studied the mechanism of action of the most active and selective sesquiterpene lactones (STLs) in L. (L.) infantum, evaluating different parameters of the parasite such as plasma membrane permeability, reactive oxygen species (ROS) content, and mitochondrial membrane potential (∆ψm ) as well as the production of nitric oxide (NO) by host cells
Our data demonstrated that 1 significantly increased the production of NO at similar levels as cells treated with LPS (Figure 5)
Summary
Leishmaniases are listed as neglected tropical diseases by the World Health Organization [1]. Natural products traditionally play an important role in search for new therapeutics Their large structural diversity of secondary metabolites is a source of novel chemical structures as starting points for drug development [7,8,9,10,11]. Natural sesquiterpene lactones (STLs) are widespread secondary metabolites in plants of the family Asteraceae [12] This class of compounds are known for a wide range of biological activities such as anticancer [13,14], gastric cytoprotective [15] and cytotoxic [16]. We studied the mechanism of action of the most active and selective STL in L. (L.) infantum, evaluating different parameters of the parasite such as plasma membrane permeability, reactive oxygen species (ROS) content, and mitochondrial membrane potential (∆ψm ) as well as the production of nitric oxide (NO) by host cells
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