Dexamethasone protects auditory hair cells against TNFα-initiated apoptosis via activation of PI3K/Akt and NFκB signaling

Scott M. Haake, Christine T. Dinh, Shibing Chen, Adrien A. Eshraghi, Thomas R. Van De Water

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Background: Tumor necrosis factor alpha (TNFα) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment). Hypothesis: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival. Materials and methods: Organ of Corti explants challenged with an ototoxic level of TNFα was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFα-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFα ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity. Results: The general caspase inhibitor Boc-d-fmk prevented TNFα-induced AHC death. There was a significant reduction (p < 0.05) in the efficacy of Dex otoprotection against TNFα ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFκB (NFκB-I). Conclusion: Dex treatment protects hair cells against TNFα apoptosis in vitro by activation of PI3K/Akt and NFκB signaling.

Original languageEnglish (US)
Pages (from-to)22-32
Number of pages11
JournalHearing Research
Volume255
Issue number1-2
DOIs
StatePublished - Sep 1 2009

Keywords

  • Apoptosis
  • Auditory hair cells
  • Dexamethasone
  • Nuclear factor kappa B
  • Organ of Corti explants
  • Otoprotection
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Sensory Systems

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