Dexamethasone protects auditory hair cells against TNFalpha-initiated apoptosis via activation of PI3K/Akt and NFkappaB signaling.

Haake SM, Dinh CT, Chen S, Eshraghi AA, Van De Water TR
Hear Res. 2009 255 (1-2): 22-32

PMID: 19442713 · DOI:10.1016/j.heares.2009.05.003

BACKGROUND - Tumor necrosis factor alpha (TNFalpha) 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 TNFalpha was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFalpha-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFalpha 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 TNFalpha-induced AHC death. There was a significant reduction (p<0.05) in the efficacy of Dex otoprotection against TNFalpha ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFkappaB (NFkappaB-I).

CONCLUSION - Dex treatment protects hair cells against TNFalpha apoptosis in vitro by activation of PI3K/Akt and NFkappaB signaling.

MeSH Terms (18)

Animals Apoptosis Benzyl Compounds Caspase Inhibitors Dexamethasone Dose-Response Relationship, Drug Hair Cells, Auditory Hydrocarbons, Fluorinated In Vitro Techniques NF-kappa B Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins c-akt Rats Rats, Sprague-Dawley Receptors, Glucocorticoid Signal Transduction Tumor Necrosis Factor-alpha

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