'Death and axes': unexpected Ca²⁺ entry phenologs predict new anti-schistosomal agents

Schistosomiasis is a parasitic flatworm disease that infects 200 million people worldwide. The drug praziquantel (PZQ) is the mainstay therapy but the target of this drug remains ambiguous. While PZQ paralyses and kills parasitic schistosomes, in free-living planarians PZQ caused an unusual axis dup...

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Published inPLoS pathogens Vol. 10; no. 2; p. e1003942
Main Authors Chan, John D, Agbedanu, Prince N, Zamanian, Mostafa, Gruba, Sarah M, Haynes, Christy L, Day, Timothy A, Marchant, Jonathan S
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.02.2014
Public Library of Science (PLoS)
Subjects
Animals
Biology
Biomedical research
Body Patterning - drug effects
Calcium Channels - drug effects
Calcium Channels - metabolism
Chromatography, High Pressure Liquid
Dopamine
Infections
Phenology
Planarians - drug effects
Praziquantel - pharmacology
Proteins
RNA Interference
Schistosoma - drug effects
Schistosomiasis
Schistosomicides - pharmacology
Tropical diseases
Worms
Schistosomiasis
Animals
Calcium Channels
RNA Interference
Praziquantel
Body Patterning
Planarians
Chromatography, High Pressure Liquid
Schistosoma
Schistosomicides
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Summary:Schistosomiasis is a parasitic flatworm disease that infects 200 million people worldwide. The drug praziquantel (PZQ) is the mainstay therapy but the target of this drug remains ambiguous. While PZQ paralyses and kills parasitic schistosomes, in free-living planarians PZQ caused an unusual axis duplication during regeneration to yield two-headed animals. Here, we show that PZQ activation of a neuronal Ca²⁺ channel modulates opposing dopaminergic and serotonergic pathways to regulate 'head' structure formation. Surprisingly, compounds with efficacy for either bioaminergic network in planarians also displayed antischistosomal activity, and reciprocally, agents first identified as antischistocidal compounds caused bipolar regeneration in the planarian bioassay. These divergent outcomes (death versus axis duplication) result from the same Ca²⁺ entry mechanism, and comprise unexpected Ca²⁺ phenologs with meaningful predictive value. Surprisingly, basic research into axis patterning mechanisms provides an unexpected route for discovering novel antischistosomal agents.
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Conceived and designed the experiments: JDC TAD JSM. Performed the experiments: JDC PNA MZ SMG. Analyzed the data: JDC PNA MZ SMG CLH. Wrote the paper: JSM.
The authors have declared that no competing interests exist.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1003942