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 language | English (US) |
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Pages (from-to) | 22-32 |
Number of pages | 11 |
Journal | Hearing Research |
Volume | 255 |
Issue number | 1-2 |
DOIs | |
State | Published - Sep 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