Effect of phospholipase A2 inhibitors during infection caused by Leishmania (Leishmania) amazonensis

Abstract

BackgroundLipid metabolites play an important role in parasite differentiation and virulence. Studies have revealed that Leishmania sp. uses prostaglandins to evade innate barriers, thus enabling the parasites to survive inside immune cells. Despite the role of the enzyme Phospholipase A2 (PLA2) in prostaglandins production, few studies have investigated the role of parasite PLA2 during the interaction between L. (L.) amazonensis and the host (in vitro and in vivo) immune cells.MethodsIn the present work, the leishmanicidal effect of PLA2 inhibitors, methyl arachidonyl fluorophosphonate (MAFP), bromoenol lactone (BEL) and aristolochic acid (AA) were investigated in vitro (promastigote and intracellular amastigote forms of L. (L.) amazonensis) and during in vivo infection using BALB/c mice.ResultsThe aforementioned inhibitors were deleterious to promastigote and amastigote forms of the L. (L.) amazonensis and were non-toxic to peritoneal macrophages from BALB/c mice. L. (L.) amazonensis-infected BALB/c mice treated with the inhibitor BEL presented decreased lesion size and skin parasitism; however, BEL treatment induced hepatotoxicity in BALB/c mice.ConclusionsResults presented herein suggested that PLA2 inhibitors altered L. (L.) amazonensis viability. In spite of liver toxicity, treatment with BEL was the most selective compound in vitro, as well in vivo, resulting in lower skin parasitism in the infected mice. These findings corroborate the role of PLA2 in parasite virulence and maintenance in vertebrate hosts, and suggest that molecules structurally related to BEL should be considered when planning compounds against Leishmania sp.

Ursolic Acid Potentializes Conventional Therapy in Experimental Leishmaniasis

“…The parasite load was determined by limiting dilution assay [ 21 , 52 ]. In VL, parasitism was quantified in the spleen and liver, while in cutaneous leishmaniasis, it was analyzed in the skin at the point of parasite inoculation.…”

Antileishmanial activity and ultrastructural changes of related tetrahydrofuran dineolignans isolated from Saururus cernuus L. (Saururaceae)

“…Based on the obtained results in this study, it is possible to suggest that both compounds 1 and 2 are interesting prototypes for the development of new drugs, since these molecules were more selective than the standard drug miltefosine, showing a selective index of 3. Other works found a different range of miltefosine SI against Leishmania species that basically is dependent on the parasite specie, strain and number of parasites in the assays among other reasons.…”

Endocytosis and Exocytosis in Leishmania amazonensis Are Modulated by Bromoenol Lactone

“…In conclusion, we showed that BEL-target activity is required for three key processes in Leishmania, namely: the internalization of nutrients by endocytosis, the secretion of vesicles and the differentiation of promastigotes into infective metacyclic forms. Interestingly, it has been shown that although their hepatotoxicity, BEL treatment decreased parasite load in a cutaneous murine model, suggesting further chemical modifications in the molecule that could decrease this side effect maintaining the leishmanicidal activity (Bordon et al, 2018).…”

“…These results prompted us to study the role of BEL in vesicular trafficking in other human pathogens from the Trypanosomatidae family, such as Leishmania amazonensis. It has been demonstrated that BEL was the most active PLA 2 inhibitor (Bordon et al, 2018), therefore we used this drug to characterize its role in some properties of promastigotes. Initially, we monitored the growth of L. amazonensis promastigotes for 7 days in Schneider's medium containing different concentrations of BEL (Figure 1A).…”