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Selective GSK-3beta inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells

Hee-Je Park1, Hyung-Jin Kim, Gi-Sang Bae

  • 1Department of Herbology, College of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, South Korea. tajohj82@hanmail.net

Hearing Research
|August 12, 2009
PubMed

Insights

Glycogen synthase kinase-3 (GSK-3) inhibitors protect auditory cells from cisplatin damage. These findings suggest GSK-3 activation contributes to cisplatin-induced ototoxicity.

Area of Science:

  • Ototoxicity research
  • Cellular and molecular biology
  • Auditory neuroscience

Background:

  • Glycogen synthase kinase-3 (GSK-3) is crucial for apoptosis regulation.
  • The role of GSK-3 in the auditory system is not well understood.
  • Cisplatin is a common chemotherapy agent known to cause ototoxicity.

Purpose of the Study:

  • To investigate the role of GSK-3 in cisplatin-induced ototoxicity.
  • To determine if GSK-3 inhibitors can protect auditory cells from cisplatin.
  • To explore the therapeutic potential of targeting GSK-3 in preventing hearing loss.

Main Methods:

  • Utilized HEI-OC1 cells and rat primary organ of Corti explants.
  • Administered GSK-3 specific inhibitors (SB 216763 and LiCl) alongside cisplatin.
  • Assessed apoptosis, caspase activation, outer hair cell survival, inflammatory cytokine production (TNF-α, IL-1β, IL-6), and auditory brainstem response (ABR) thresholds in cisplatin-injected mice.

Main Results:

  • Cisplatin treatment activated GSK-3 in HEI-OC1 cells.
  • SB 216763 and LiCl inhibited cisplatin-induced apoptosis and caspase activation in a dose-dependent manner.
  • GSK-3 inhibitors prevented outer hair cell destruction, reduced cochlear inflammation, and improved ABR thresholds in mice.
  • Cisplatin-induced ototoxicity was linked to GSK-3 activation.

Conclusions:

  • GSK-3 activation is implicated in cisplatin-induced ototoxicity.
  • GSK-3 inhibitors demonstrate a protective effect against cisplatin-induced auditory cell damage.
  • Targeting GSK-3 activation presents a potential therapeutic strategy for mitigating chemotherapy-induced hearing loss.

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