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JNK signaling in neomycin-induced vestibular hair cell death

Kazuma Sugahara1, Edwin W Rubel, Lisa L Cunningham

  • 1Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA 98195-7923, USA.

Hearing Research
|September 29, 2006
PubMed

Insights

The c-Jun n-terminal kinase (JNK) pathway contributes to aminoglycoside-induced hair cell death. Inhibiting JNK signaling protects vestibular hair cells from neomycin toxicity, suggesting JNK as a therapeutic target.

Area of Science:

  • Ototoxicity research
  • Cellular stress response
  • Neuroscience

Background:

  • Mechanosensory hair cells are vulnerable to apoptosis from ototoxic drugs like aminoglycosides.
  • The c-Jun n-terminal kinase (JNK) signaling pathway is implicated in promoting apoptotic cell death.
  • JNK pathway inhibition shows potential in preventing aminoglycoside-induced hair cell death in auditory and vestibular systems.

Purpose of the Study:

  • To investigate the role of JNK activation in aminoglycoside-induced hair cell death using an in vitro mouse utricle model.
  • To assess the efficacy of an indirect JNK inhibitor, CEP-11004, in preventing neomycin-induced hair cell death.
  • To explore the downstream effects of JNK inhibition on apoptotic pathways, specifically caspase-9 activation.

Main Methods:

  • Utilized an in vitro preparation of adult mouse utricles.
  • Administered neomycin to induce hair cell death and CEP-11004 as a JNK inhibitor.
  • Employed immunohistochemistry to detect phosphorylated JNK and c-Jun.
  • Assessed hair cell survival across different neomycin doses.
  • Investigated the involvement of PKC and p38 pathways.
  • Examined caspase-9 activation in response to JNK inhibition.

Main Results:

  • Neomycin exposure led to phosphorylation of JNK and c-Jun in hair cells.
  • CEP-11004 successfully inhibited neomycin-induced phosphorylation of JNK and c-Jun.
  • CEP-11004 demonstrated a protective effect against hair cell death at moderate neomycin doses but not at high doses.
  • The protective effect was specific to JNK inhibition, as other kinase inhibitors did not replicate it.
  • JNK inhibition also suppressed the activation of caspase-9 in hair cells.

Conclusions:

  • JNK signaling plays a significant role in neomycin-induced vestibular hair cell death.
  • Inhibition of JNK pathway activation can protect against ototoxicity, particularly at moderate drug concentrations.
  • JNK-mediated apoptosis in hair cells involves the activation of caspase-9.
  • Targeting the JNK pathway presents a potential therapeutic strategy for preventing aminoglycoside-induced hearing loss and balance disorders.

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