title: Towards an understanding of the mechanism of action of praziquantel.
abstract: Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of Schistosoma mansoni PR-1 to heat shock to confirm that while 6-week post-infection (p.i.) schistosomes are sensitive to PZQ, 4-week p.i. schistosomes are not. Further, we have used this assay to demonstrate that in mice this sensitivity develops between days 37 and 40 p.i. When PZQ is linked to the fluorophore BODIPY to aid microscopic visualization, it appears to enter the cells of intact 4 and 6-week p.i. schistosomes as well as mammalian NIH 3T3 cells with ease suggesting that the differential effects of PZQ is not based on cell exclusion. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 up-regulated candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress.
authors.affiliation: Center for Evolutionary and Theoretical Immunology, Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Aragon
authors.forename: Reza A
authors.initials: RA
authors.lastname: Imani
authors.forename: Vint R
authors.initials: VR
authors.lastname: Blackburn
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Cupit
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Melman
authors.forename: Tinopiwa
authors.initials: T
authors.lastname: Goronga
authors.forename: Thomas
authors.initials: T
authors.lastname: Webb
authors.forename: Eric S
authors.initials: ES
authors.lastname: Loker
authors.forename: Charles
authors.initials: C
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017238:Genes, Helminth / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D021261:Parasitic Sensitivity Tests; D011223:Praziquantel / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D012552:Schistosomiasis / Q000188:drug therapy; D013997:Time Factors
chemical_list: D000871:Anthelmintics; D006360:Heat-Shock Proteins; D011223:Praziquantel