Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel

Abstract

BackgroundSchistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. This parasitic disease is due to immunologic reactions to Schistosoma eggs trapped in tissues. Egg-released antigens stimulate tissue-destructive inflammatory and granulomatous reactions, involving different immune cell populations, including T cells and granulocytes. Granulomas lead to collagen fibers deposition and fibrosis, resulting in organ damage. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis.Methodology/Principal FindingsUsing in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity. The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals.Conclusions/SignificanceTaken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.

Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine

“…The finding that edelfosine diminishes the capacity of macrophages to mount an inflammatory response might be relevant, as severe inflammation at the site of infection leads to tissue destruction in leishmaniasis [ 60 ]. In this regard, edelfosine has also been reported to display a potent anti-inflammatory action through L-selectin shedding in human neutrophils, thus preventing neutrophil extravasation [ 31 ], and recent in vivo evidence further supports the anti-inflammatory and immunomodulatory effect of edelfosine [ 61 – 63 ]. Furthermore, edelfosine promotes apoptosis in mitogen-activated T lymphocytes [ 64 ].…”

An efficient method to isolate Kupffer cells eliminating endothelial cell contamination and selective bias

“…However, we acknowledge that there is considerable variation reported in number and speed of centrifugations, as well as gradient concentrations used in protocols to isolate liver leukocytes. 11,13,28,29 Nevertheless, our data suggest that careful optimization of these methods will be required for studies where KCs are the major cell of interest.…”

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

“…Thus, edelfosine has been found to promote apoptosis in activated lymphocytes (Cabaner, et al, 1999), hence suggesting a role for this drug in the treatment of autoimmune diseases (Abramowski, et al, 2014;Mollinedo, 2007). In addition, in vitro and in vivo assays in animal models have shown that edelfosine is a potent anti-inflammatory agent , as well as an effective drug against leishmaniasis Varela, et al, 2012) and schistosomiasis (Yepes, et al, 2014;Yepes, et al, 2015). Additional biomedical applications and patents for…”