title: Dexamethasone protects auditory hair cells against TNFalpha-initiated apoptosis via activation of PI3K/Akt and NFkappaB signaling.
abstract: 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).
  
  
  OBJECTIVE
  Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival.
  
  
  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).
  
  
  CONCLUSIONS
  Dex treatment protects hair cells against TNFalpha apoptosis in vitro by activation of PI3K/Akt and NFkappaB signaling.
authors.affiliation: Cochlear Implant Research Program, University of Miami Ear Institute, Department of Otolaryngology, University of Miami, Miller School of Medicine, RMSB 3160, Miami, FL 33136-1015, USA. shaake@med.miami.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Haake
authors.forename: Christine T
authors.initials: CT
authors.lastname: Dinh
authors.forename: Shibing
authors.initials: S
authors.lastname: Chen
authors.forename: Adrien A
authors.initials: AA
authors.lastname: Eshraghi
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Van De Water
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001593:Benzyl Compounds / Q000494:pharmacology; D061945:Caspase Inhibitors; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D066298:In Vitro Techniques; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001593:Benzyl Compounds; D061945:Caspase Inhibitors; D003907:Dexamethasone; D006845:Hydrocarbons, Fluorinated; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C476029:Boc-D-FMK