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      Discovery and Characterization of Novel Anti-schistosomal Properties of the Anti-anginal Drug, Perhexiline and Its Impact on Schistosoma mansoni Male and Female Reproductive Systems

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          Abstract

          Background

          Schistosomiasis, one of the world’s greatest human neglected tropical diseases, is caused by parasitic trematodes of the genus Schistosoma. A unique feature of schistosome biology is that the induction of sexual maturation as well as the maintenance of the differentiation status of female reproductive organs and egg production, necessary for both disease transmission and pathogenesis, are strictly dependent on the male. The treatment and most control initiatives of schistosomiasis rely today on the long-term application of a single drug, praziquantel (PZQ), mostly by campaigns of mass drug administration. PZQ, while very active on adult parasites, has much lower activity against juvenile worms. Monotherapy also favors the selection of drug resistance and, therefore, new drugs are urgently needed.

          Methods and Findings

          Following the screening of a small compound library with an ATP-based luminescent assay on Schistosoma mansoni schistosomula, we here report the identification and characterization of novel antischistosomal properties of the anti-anginal drug perhexiline maleate (PHX). By phenotypic worm survival assays and confocal microscopy studies we show that PHX, in vitro, has a marked lethal effect on all S. mansoni parasite life stages (newly transformed schistosomula, juvenile and adult worms) of the definitive host. We further demonstrate that sub-lethal doses of PHX significantly impair egg production and lipid depletion within the vitellarium of adult female worms. Moreover, we highlighted tegumental damage in adult male worms and remarkable reproductive system alterations in both female and male adult parasites. The in vivo study in S. mansoni-patent mice showed a notable variability of worm burdens in the individual experiments, with an overall minimal schistosomicidal effect upon PHX treatment. The short PHX half-life in mice, together with its very high rodent plasma proteins binding could be the cause of the modest efficacy of PHX in the schistosomiasis murine model.

          Conclusions/Significance

          Overall, our data indicate that PHX could represent a promising starting point for novel schistosomicidal drug discovery programmes.

          Author Summary

          Schistosomiasis is one of the 17 neglected tropical diseases prioritized by the World Health Organization. It affects hundreds of millions of people in developing countries in the poorest tropical and subtropical regions of the world. Today, essentially a single drug, praziquantel (PZQ), is available to treat this parasitic disease. PZQ incomplete efficacy across all stages of the Schistosoma mansoni life cycle in the definitive host and the potential risk of drug resistance prompted us to search for novel schistosomicidal molecules. We screened a compound collection library using the larval stage of the parasite and discovered novel anti-schistosomal properties of perhexiline maleate (PHX). Overall, our study demonstrated that the anti-anginal drug PHX, still used in some countries, is active in vitro against parasite life stages poorly sensitive to PZQ. In addition, we showed that PHX impairs egg production in mature worm couples in vitro and damages the female and male reproductive systems and the male worm tegument. PHX could therefore represent a promising starting point for novel schistosomicidal drug discovery programmes.

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          Most cited references46

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          Myocardial fatty acid metabolism in health and disease.

          There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the beta-oxidation of long-chain fatty acids. The control of fatty acid beta-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via beta-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and beta-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid beta-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid beta-oxidation and how alterations in fatty acid beta-oxidation can contribute to heart disease. The implications of inhibiting fatty acid beta-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.
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            Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment.

            The efficacy of praziquantel against a Puerto Rican strain of Schistosoma mansoni was assessed using both in vivo and in vitro approach. The drug effective dose (50%) in the infected mouse model was about 30 times higher when determined against 28-day-old infections than against 7-week-old parasites. Single-sex female infections were also largely refractory to treatment and single-sex male infections moderately refractory, in comparison with bisexual infections. The in vitro approach consisted of overnight exposure of parasite cultures to various drug concentrations, followed by several days of culture in drug-free medium. In vitro results confirmed in vivo data and allowed for the observation of schistosome morphological phenomena after praziquantel exposure. Early worm contraction was observed in all cases, even after exposure to sub-lethal concentrations of praziquantel or upon exposure of the largely refractory 28-day-old schistosomes. In these instances, however, worms resumed movements and normal shape upon drug removal and were able to survive. The inference of these observations on the clinical use of praziquantel and on its mechanism of action is discussed.
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              Drug-resistant schistosomiasis: resistance to praziquantel and oxamniquine induced in Schistosoma mansoni in mice is drug specific.

              Schistosoma mansoni infections in mice were treated with subcurative multiple doses of either praziquantel (PZQ) or oxamniquine (OX). With an early exception, the drug treatments commenced when the worms were adult, but before the infections had become fully patent, and the eggs subsequently produced by worms that had survived the drug treatments were used to infect snails. Six or seven drug-treated passages of S. mansoni in mice were completed for each of the drugs, with the amount of drug administered to the infected mice generally being increased with each passage. Eighty percent of the worms of the sixth passage selected for PZQ resistance survived three doses of 300 mg/kg of PZQ given between days 28 and 37 after infection, and 93% of those of the seventh passage survived the same drug dose. In contrast, only 13% of worms of the sixth PZQ-selected passage survived three doses of 200mg/kg of OX given during the same period after infection. Only 11% or fewer worms derived from S. mansoni infections that had not been subjected to any drug pressure survived the 3 x 300 mg/kg PZQ treatments. Worms selected for OX resistance over six passages were completely resistant to three doses of 200 mg/kg, but only 26% survived three doses of 300 mg/kg of PZQ. Therefore, the results indicate that S. mansoni subjected to drug pressure may develop resistance to schistosomicidal drugs over the course of relatively few passages, but that cross-resistance between PZQ and OX does not occur. This is the first demonstration of drug resistance to PZQ, the current drug of choice for human schistosomiasis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                12 August 2016
                August 2016
                : 10
                : 8
                : e0004928
                Affiliations
                [1 ]National Research Council, Institute of Cell Biology and Neurobiology, Campus A. Buzzati-Traverso Monterotondo, Roma, Italy
                [2 ]European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo, Italy
                [3 ]IRBM Science Park, Department of Preclinical Research, Pomezia, Italy
                [4 ]IRBM Science Park, Department of Biology, Pomezia, Italy
                University of Pennsylvania, UNITED STATES
                Author notes

                We have read the journal's policy and the authors of this manuscript have the following competing interests. We declare that AG, CL, GR and AB have pending patent pertinent to this article (PCT/EP2015/066264). We confirm that this does not alter our adherence to all PLoS Neglected Tropical Diseases journal policies on sharing data and materials.

                • Conceived and designed the experiments: AG CL GR.

                • Performed the experiments: AG CL EP GB MN.

                • Analyzed the data: AG CL EM AB GR.

                • Wrote the paper: AG GR.

                Article
                PNTD-D-16-00551
                10.1371/journal.pntd.0004928
                4982595
                27518281
                c004ced2-e34e-4b8b-8353-56b57dace9ab
                © 2016 Guidi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 March 2016
                : 26 July 2016
                Page count
                Figures: 12, Tables: 1, Pages: 22
                Funding
                This work was partially supported by the CNR (National Research Council)-CNCCS (Collezione Nazionale di Composti Chimici e Centro di screening) Project “Rare, Neglected and Poverty Related Diseases - Schistodiscovery”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Animals
                Invertebrates
                Helminths
                Schistosoma
                Schistosoma Mansoni
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                Sperm
                Medicine and Health Sciences
                Parasitic Diseases
                Medicine and Health Sciences
                Parasitic Diseases
                Helminth Infections
                Schistosomiasis
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Schistosomiasis
                Biology and Life Sciences
                Biochemistry
                Lipids
                Biology and Life Sciences
                Biochemistry
                Proteins
                Plasma Proteins
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                OVA
                Oocytes
                Research and Analysis Methods
                Microscopy
                Light Microscopy
                Confocal Microscopy
                Confocal Laser Microscopy
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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