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

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.