The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel

Toxicol Appl Pharmacol. 2017 Dec 1;336:55-65. doi: 10.1016/j.taap.2017.10.012. Epub 2017 Oct 18.

Abstract

Praziquantel is the most effective anthelminthic drug for the treatment of schistosomiasis, an infectious disease caused by the platyhelminth Schistosoma mansoni. While praziquantel is known to trigger calcium influx into schisostomes, followed by spastic paralysis of the worms and tegumental disruption, the mechanism of action of the drug is not completely understood. Although relatively well tolerated, praziquantel has been reported to cause mild adverse effects, including nausea, abdominal pain and headaches. As a number of putative Transient Receptor Potential (TRP) channel genes have recently been predicted in S. mansoni, we sought to investigate the effect of praziquantel on three mammalian TRP channels, TRP melastatin type 8 (TRPM8), TRP vanilloid type 1 (TRPV1) and TRP ankyrin type 1 (TRPA1). Using calcium microfluorimetry and the patch clamp technique, we recorded the effect of praziquantel on HEK293T cells expressing recombinant TRPM8, TRPV1 or TRPA1, as well as on cultured dorsal root ganglion (DRG) neurons from wild type and TRPM8 null mutant mice. We discovered that praziquantel is a relatively potent and selective partial agonist of the mammalian and avian cold and menthol receptor TRPM8. The activation of cultured DRG neurons by clinically relevant concentrations of praziquantel is predominantly mediated by TRPM8. Our results may provide clues to a better understanding of praziquantel's mechanism of action and its adverse effects.

Keywords: Calcium imaging; Dorsal root ganglion; Praziquantel; Schisostoma mansoni; Transient Receptor Potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Anthelmintics / pharmacology*
  • Anthelmintics / toxicity
  • Calcium Signaling / drug effects
  • Dose-Response Relationship, Drug
  • Drug Partial Agonism
  • Ganglia, Spinal / drug effects*
  • Ganglia, Spinal / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Potentials
  • Menthol / analogs & derivatives
  • Menthol / pharmacology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Praziquantel / pharmacology*
  • Praziquantel / toxicity
  • Rats, Wistar
  • TRPM Cation Channels / agonists*
  • TRPM Cation Channels / deficiency
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism
  • Transfection

Substances

  • Anilides
  • Anthelmintics
  • N-(4-methoxyphenyl)-4-menthone-3-carboxamide
  • TRPM Cation Channels
  • TRPM8 protein, human
  • TRPM8 protein, mouse
  • Trpm8 protein, rat
  • Menthol
  • Praziquantel