Investigation of the Anti-Leishmania (Leishmania) infantum Activity of Some Natural Sesquiterpene Lactones

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.

Benzoic Acid Derivatives of Ifloga spicata (Forssk.) Sch.Bip. as Potential Anti-Leishmanial against Leishmania tropica

“…The Leishmania plasma membrane regulates the passage of nutrients, and the homeostasis, to maintain viability. SYTOX dye is a nucleic acid stain which combines with DNA, increasing the fluorescence up to 500-fold, which is observed as a green color [19,39,51].…”

Primary targets of the sesquiterpene lactone deoxymikanolide on Trypanosoma cruzi

“…Based on a previous report about the in vitro and in vivo trypanocidal activity of deoxymikanolide, this compound was selected to carry out a biochemical characterization of its mechanism of action. Even though the presence of an α-β unsaturated lactone moiety is a common structural feature among STLs to which most of their biological activities are attributed, different antiprotozoal mechanisms of action have been described for them (Sülsen et al, 2010;Sülsen et al, 2016;Wulsten et al, 2017).…”

Arnica Tincture Cures Cutaneous Leishmaniasis in Golden Hamsters

“…It will also be of interest to investigate whether the total extract present in the tincture is superior in activity to isolated STL, i.e., helenalin and 11α,13-dihydrohelenalin esters. These compounds are known to possess antileishmanial activity [ 2 , 3 , 4 ] but it is quite likely that their proven anti-inflammatory activity [ 5 , 6 , 7 ] also contributes to the curative effects observed in the present CL model.…”

“…One of the preparations tested in this work was a commercial Arnica tincture which showed high activity against Trypanosoma brucei but also considerable growth inhibitory activity on Leishmania donovani , one of the pathogens causing visceral Leishmaniasis. In previous studies, considerable in vitro activity against protozoan parasites had been reported for single consitutents of Arnica, namely, sesquiterpene lactones (STLs) of the helenalin type [ 2 , 3 , 4 ]. Arnica tincture and other preparations from the same plant material are commonly used as safe and efficacious topical treatment for inflammatory conditions of the skin, joints or muscles [ 5 ] which has been mainly attributed to its STLs and their inhibitory activity on inflammatory transcription factor NF-κB [ 6 ].…”