A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel beta subunits: subversion of flatworm regenerative polarity

PLoS Negl Trop Dis. 2009 Jun 23;3(6):e464. doi: 10.1371/journal.pntd.0000464.

Abstract

Background: Approximately 200 million people worldwide harbour parasitic flatworm infections that cause schistosomiasis. A single drug-praziquantel (PZQ)-has served as the mainstay pharmacotherapy for schistosome infections since the 1980s. However, the relevant in vivo target(s) of praziquantel remain undefined.

Methods and findings: Here, we provide fresh perspective on the molecular basis of praziquantel efficacy in vivo consequent to the discovery of a remarkable action of PZQ on regeneration in a species of free-living flatworm (Dugesia japonica). Specifically, PZQ caused a robust (100% penetrance) and complete duplication of the entire anterior-posterior axis during flatworm regeneration to yield two-headed organisms with duplicated, integrated central nervous and organ systems. Exploiting this phenotype as a readout for proteins impacting praziquantel efficacy, we demonstrate that PZQ-evoked bipolarity was selectively ablated by in vivo RNAi of voltage-operated calcium channel (VOCC) beta subunits, but not by knockdown of a VOCC alpha subunit. At higher doses of PZQ, knockdown of VOCC beta subunits also conferred resistance to PZQ in lethality assays.

Conclusions: This study identifies a new biological activity of the antischistosomal drug praziquantel on regenerative polarity in a species of free-living flatworm. Ablation of the bipolar regenerative phenotype evoked by PZQ via in vivo RNAi of VOCC beta subunits provides the first genetic evidence implicating a molecular target crucial for in vivo PZQ activity and supports the 'VOCC hypothesis' of PZQ efficacy. Further, in terms of regenerative biology and Ca(2+) signaling, these data highlight a novel role for voltage-operated Ca(2+) entry in regulating in vivo stem cell differentiation and regenerative patterning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anthelmintics / pharmacology*
  • Calcium Channels / metabolism*
  • Gene Silencing
  • Platyhelminths / drug effects*
  • Praziquantel / pharmacology*
  • Protein Subunits / metabolism
  • RNA, Small Interfering / genetics
  • Regeneration / drug effects*

Substances

  • Anthelmintics
  • Calcium Channels
  • Protein Subunits
  • RNA, Small Interfering
  • Praziquantel