Chemical chaperone 4-phenylbutyrate prevents hearing loss and cochlear hair cell death in Cdh23erl/erl mutant mice

Neuroreport. 2019 Feb 6;30(3):145-150. doi: 10.1097/WNR.0000000000001173.

Abstract

We previously developed Cdh23 mutant mice (erl mice) as a model of hearing loss for otoprotective drug evaluation and showed that the erl mutation leads to hearing loss related to endoplasmic reticulum (ER) stress-induced cochlear hair cell apoptosis. Small molecular chemical chaperones, 4-phenylbutyrate (4PBA), targeting ER stress exert a neuroprotective effect. To evaluate whether 4PBA exerts an otoprotective effect, we intraperitoneally injected erl mice with 4PBA daily from postnatal age day 7 up to 12 weeks. Our results showed that treatment with 4PBA significantly alleviated hearing loss and suppressed hair cell death in erl mice. In addition, ER stress-related proteins were downregulated by 4PBA treatment. Our study showed that 4PBA exerts an otoprotective effect, which provides the potential to repurpose the drug for otoprotection.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cadherins / genetics*
  • Cell Death / drug effects
  • Cell Death / genetics
  • Deafness / drug therapy
  • Deafness / genetics
  • Endoplasmic Reticulum Stress / drug effects
  • Hair Cells, Auditory / drug effects*
  • Hearing Loss / drug therapy*
  • Mice, Inbred C57BL
  • Molecular Chaperones / genetics
  • Mutation / genetics
  • Phenylbutyrates / pharmacology*

Substances

  • Cadherins
  • Cdh23 protein, mouse
  • Molecular Chaperones
  • Phenylbutyrates
  • 4-phenylbutyric acid