title: Conservation of hearing and protection of auditory hair cells against trauma-induced losses by local dexamethasone therapy: molecular and genetic mechanisms.
abstract: OBJECTIVE
  Dexamethasone (DXM) protects hearing against trauma-induced loss.
  
  
  METHODS
  in vivo: A guinea pig model of electrode induced trauma (EIT)-induced hearing loss was used to locally deliver dexamethasone. In vitro: TNF-α-challenged organ of Corti explants treated with DXM or polymer-eluted DXM +/- PI3K/Akt/PkB/NFkB inhibitors were used for hair cells count and gene expression studies.
  
  
  RESULTS
  in vivo: local DXM treatment of EIT-animals prevents trauma-induced loss of ABR thresholds that occurs in EIT-animals and EIT-animals treated with the carrier solution (i.e., AP), and prevented loss of auditory hair cells. In vitro: DXM and polymer-eluted DXM were equally effective in protecting hair cells from ototoxic levels of TNF-α Inhibitor treated explants demonstrated that DXM treatment requires both Akt/PKB and NFkB signalling for otoprotection. DXM treatment of explants showed up regulation of anti-apoptosis related genes (i.e., Bcl-2, Bcl-xl) and down regulation of pro-apoptosis related genes (i.e., Bax, TNFR-1).
  
  
  CONCLUSIONS
  DXM exert its otoprotective action by activation of cell signal molecules (e.g., NFkB) that alter the expression of anti- and pro-apoptosis genes.
authors.affiliation: Cochlear Implant Research Program, University of Miami Ear Institute, Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136-1015, USA. tvandewater@med.miami.edu
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Van De Water
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Abi Hachem
authors.forename: Christine T
authors.initials: CT
authors.lastname: Dinh
authors.forename: Esperanza
authors.initials: E
authors.lastname: Bas
authors.forename: Scott M
authors.initials: SM
authors.lastname: Haake
authors.forename: Gia
authors.initials: G
authors.lastname: Hoosien
authors.forename: Richard
authors.initials: R
authors.lastname: Vivero
authors.forename: Sherry
authors.initials: S
authors.lastname: Chan
authors.forename: Jao
authors.initials: J
authors.lastname: He
authors.forename: Adrien A
authors.initials: AA
authors.lastname: Eshraghi
authors.forename: Simon I
authors.initials: SI
authors.lastname: Angeli
authors.forename: Fred F
authors.initials: FF
authors.lastname: Telischi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Balkany
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001309:Auditory Threshold / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004567:Electrodes, Implanted / Q000009:adverse effects; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects*; D034381:Hearing Loss / Q000209:etiology / Q000517:prevention & control*; D066298:In Vitro Techniques; D009925:Organ of Corti / Q000187:drug effects; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000494:pharmacology; D015854:Up-Regulation; D014947:Wounds and Injuries / Q000150:complications
chemical_list: C082659:ABR protein, human; D020690:GTPase-Activating Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone