Revealing praziquantel molecular targets using mass spectrometry imaging: an expeditious approach applied to Schistosoma mansoni

Ferreira, Mônica Siqueira; Oliveira, Rosimeire Nunes de; Oliveira, Diogo Noin de; Esteves, Cibele Zanardi; Allegretti, Silmara Marques; Catharino, Rodrigo Ramos

doi:10.1016/j.ijpara.2014.12.008

Cited by 21 publications

(18 citation statements)

References 59 publications

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“…The researchers were able to characterize both sexes of S. mansoni adult worms (BH strain) treated with PZQ and identified the spatial distribution of chemical markers. In addition to tegumental damage, PZQ significantly changed the metabolic profile of both sexes of S. mansoni [49]. These data are supported by a recent work where tegumental damage of schistosomes under PZQ exposure was demonstrated through scanning electronic microscopy and optical microscopy [92].…”

Section: Searching For Drug Targets At Helminthiasis-praziquantel Andsupporting

confidence: 80%

“…Molecular detailed analysis of the diverse A. lumbricoides forms may elucidate new targets for parasite control. Metabolic fingerprinting using mass spectrometry has been widely employed, targeting parasite-related metabolites [34,49,50]. The trend of establishing target molecules and linking them with important metabolic pathways in the parasite life cycle broadens the knowledge in the field, generating a platform that will assist in better knowledge on their biology, elucidation of survival mechanisms, pharmacodynamics, diagnostic methodologies, development of pharmaceutical products to eradicate these diseases, whether in soil or living hosts, etc.…”

Section: Ascaris Lumbricoides and Chemical Markers At Moulting Processmentioning

confidence: 99%

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Mass Spectrometry and Metabolomics—New Approaches for Helminth Biochemical Studies

Lima¹,

Esteves²,

Oliveira³

et al. 2017

Human Helminthiasis

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Metabolomics, the study of the endogenously synthesized small molecules repertoire (nonproteinaceous), is of great relevance for establishing a wide view of cell physiology at specific moments, linking metabolic profiles to phenotypes and genotypes. To better understand biological systems, such as helminths life cycle, helminthic infection, and host-parasite interaction, metabolomics studies are crucial. For that, mass spectrometrybased metabolomics is the most popular strategy. Nontargeted metabolomics allows researchers to profile entire metabolomes present in cells, tissues, biofluids, or even samples as complex as stools. Through different mass spectrometric techniques, it is possible to unveil chemical markers for helminths, such as Schistosoma mansoni (a trematode) and Ascaris lumbricoides (a nematode), in addition to study mechanisms of action for different drugs, which targets parasites. Therefore, mass spectrometry allows designing biochemical pathways that may clarify the processes of parasite life cycle, helminthic infection, and host-parasite interaction, providing targets to further interference for parasite control or even infection treatment.

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Section: Searching For Drug Targets At Helminthiasis-praziquantel Andsupporting

confidence: 80%

Section: Ascaris Lumbricoides and Chemical Markers At Moulting Processmentioning

confidence: 99%

Mass Spectrometry and Metabolomics—New Approaches for Helminth Biochemical Studies

Lima¹,

Esteves²,

Oliveira³

et al. 2017

Human Helminthiasis

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show abstract

“…The mechanism of action and molecular targets of Praziquantel are unknown. However many studies have reported vacuolation and blebbing of worm teguments and suggested a direct disruptive effect on Ca 2+ channels, whereas a recent work has described distinct effects on male and female worms [ 10 , 11 ]. Although effective even at a single dose, reinfection is frequent and in 2013 only 13% of people necessitating treatment could benefit from it [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosmiasis

Masi

Perles-Barbacaru

Laprie³

et al. 2015

PLoS Negl Trop Dis

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BackgroundSchistosomiasis (or bilharzia), a major parasitic disease, affects more than 260 million people worldwide. In chronic cases of intestinal schistosomiasis caused by trematodes of the Schistosoma genus, hepatic fibrosis develops as a host immune response to the helminth eggs, followed by potentially lethal portal hypertension. In this study, we characterized hepatic and splenic features of a murine model of intestinal schistosomiasis using in vivo magnetic resonance imaging (MRI) and evaluated the transverse relaxation time T2 as a non-invasive imaging biomarker for monitoring hepatic fibrogenesis.Methodology/Principal FindingsCBA/J mice were imaged at 11.75T two, six and ten weeks after percutaneous infection with Schistosoma mansoni. In vivo imaging studies were completed with histology at the last two time points. Anatomical MRI allowed detection of typical manifestations of the intestinal disease such as significant hepato- and splenomegaly, and dilation of the portal vein as early as six weeks, with further aggravation at 10 weeks after infection. Liver multifocal lesions observed by MRI in infected animals at 10 weeks post infection corresponded to granulomatous inflammation and intergranulomatous fibrosis with METAVIR scores up to A2F2. While most healthy hepatic tissue showed T2 values below 14 ms, these lesions were characterized by a T2 greater than 16 ms. The area fraction of increased T2 correlated (rS = 0.83) with the area fraction of Sirius Red stained collagen in histological sections. A continuous liver T2* decrease was also measured while brown pigments in macrophages were detected at histology. These findings suggest accumulation of hematin in infected livers.Conclusions/SignificanceOur multiparametric MRI approach confirms that this murine model replicates hepatic and splenic manifestations of human intestinal schistosomiasis. Quantitative T2 mapping proved sensitive to assess liver fibrogenesis non-invasively and may therefore constitute an objective imaging biomarker for treatment monitoring in diseases involving hepatic fibrosis.

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“…Apparently, PZQ1 alters the conformation of the usual surface double lipid bilayer that surrounds schistosomes (78). Perhaps PZQ1 inhibits sphingomyelinase activity and thereby impairs reproduction by impeding the continuous release of eggs (79,80). Despite these efforts to understand how PZQ1 acts, the molecular targets remain elusive.…”

Section: How Does Pzq Kill Schistosomes?mentioning

confidence: 99%

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Vale

Gouveia

Rinaldi

et al. 2017

Antimicrob Agents Chemother

283

244

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Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drugresistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

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Revealing praziquantel molecular targets using mass spectrometry imaging: an expeditious approach applied to Schistosoma mansoni

Cited by 21 publications

References 59 publications

Mass Spectrometry and Metabolomics—New Approaches for Helminth Biochemical Studies

Mass Spectrometry and Metabolomics—New Approaches for Helminth Biochemical Studies

In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosmiasis

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

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