TRPV4 inhibition prevents paclitaxel-induced neurotoxicity in preclinical models

Exp Neurol. 2018 Aug;306:64-75. doi: 10.1016/j.expneurol.2018.04.014. Epub 2018 Apr 30.

Abstract

Paclitaxel is a cytotoxic drug which frequently causes sensory peripheral neuropathy in patients. Increasing evidence suggests that altered intracellular calcium (Ca2+) signals play an important role in the pathogenesis of this condition. In the present study, we examined the interplay between Ca2+ release channels in the endoplasmic reticulum (ER) and Ca2+ permeable channels in the plasma membrane in the context of paclitaxel mediated neurotoxicity. We observed that in small to medium size dorsal root ganglia neurons (DRGN) the inositol-trisphosphate receptor (InsP3R) type 1 was often concentrated in the periphery of cells, which is in contrast to homogenous ER distribution. G protein-coupled designer receptors were used to further elucidate phosphoinositide mediated Ca2+ signaling: This approach showed strong InsP3 mediated Ca2+ signals close to the plasma membrane, which can be amplified by Ca2+ entry through TRPV4 channels. In addition, our results support a physical interaction and partial colocalization of InsP3R1 and TRPV4 channels. In the context of paclitaxel-induced neurotoxicity, blocking Ca2+ influx through TRPV4 channels reduced cell death in cultured DRGN. Pretreatment of mice with the pharmacological TRPV4 inhibitor HC067047 prior to paclitaxel injections prevented electrophysiological and behavioral changes associated with paclitaxel-induced neuropathy. In summary, these results underline the relevance of TRPV4 signaling for the pathogenesis of paclitaxel-induced neuropathy and suggest novel preventive strategies.

Keywords: Calcium; Inositol-trisphosphate receptor; Neuropathy; Paclitaxel; TRPV4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / toxicity*
  • Calcium Channels / drug effects
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects
  • Cell Death / drug effects
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Ganglia, Spinal / pathology
  • Immunohistochemistry
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Mice, Inbred C57BL
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / prevention & control*
  • Paclitaxel / toxicity*
  • Rats
  • Rats, Wistar
  • TRPV Cation Channels / antagonists & inhibitors*
  • Transfection

Substances

  • Antineoplastic Agents, Phytogenic
  • Calcium Channels
  • Inositol 1,4,5-Trisphosphate Receptors
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Trpv4 protein, rat
  • Paclitaxel