title: 'Death and axes': unexpected Ca²⁺ entry phenologs predict new anti-schistosomal agents.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Chan
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Prince N
authors.initials: PN
authors.lastname: Agbedanu
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Zamanian
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Gruba
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Christy L
authors.initials: CL
authors.lastname: Haynes
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Day
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America ; The Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Marchant
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000187:drug effects*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D010932:Planarians / Q000187:drug effects; D011223:Praziquantel / Q000494:pharmacology*; D034622:RNA Interference; D012547:Schistosoma / Q000187:drug effects*; D012552:Schistosomiasis; D012556:Schistosomicides / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D012556:Schistosomicides; D011223:Praziquantel