title: Molecular mechanisms involved in cochlear implantation trauma and the protection of hearing and auditory sensory cells by inhibition of c-Jun-N-terminal kinase signaling.
abstract: OBJECTIVE
  To investigate the molecular mechanisms involved in electrode insertion trauma (EIT) and to test the otoprotective effect of locally delivered AM-111.
  
  
  METHODS
  An animal model of cochlear implantation.
  
  
  METHODS
  Guinea pigs' hearing thresholds were measured by auditory brainstem response (ABR) before and after cochlear implantation in four groups: EIT; pretreated with hyaluronate gel 30 minutes before EIT (EIT+Gel); pretreated with hyaluronate gel/AM-111 30 minutes before EIT (EIT+AM-111); and unoperated contralateral ears as controls. Neurofilament, synapsin, and fluorescein isothiocyanate (FITC)-phalloidin staining for hair cell counts were performed at 90 days post-EIT. Immunostaining for 4-hydroxy-2-nonenal (HNE), activated caspase-3, CellROX, and phospho-c-Jun were performed at 24 hours post-EIT.
  
  
  RESULTS
  ABR thresholds increased post-EIT in the cochleae of EIT only and EIT+Gel treated animals. There was no significant increase in hearing thresholds in cochleae from either EIT+AM-111 treated or unoperated control ears. AM-111 protection of organ of Corti sensory elements (i.e., hair cells [HCs], supporting cells [SCs], nerve fibers, and synapses) was documented at 3 months post-EIT. Immunostaining of 24-hour post-EIT specimens demonstrated increased levels of HNE in HCs and SCs; increased levels of CellROX and activation of caspase-3 was observed only in SCs, and phosphorylation of c-Jun occurred only in HCs of the EIT-only and EIT+Gel specimens. There was no immunostaining for either HNE, CellROX, caspase-3, or phospho-c-Jun in the organ of Corti specimens from AM-111 treated cochleae.
  
  
  CONCLUSIONS
  Molecular mechanisms involved in programmed cell death of HCs are different than the ones involved in programmed cell death of SCs. Local delivery of AM-111 provided a significant level of protection against EIT-induced hearing losses, HC losses, and damage to neural elements.
authors: University of Miami Hearing Research Laboratory, Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida 33136-1015, USA. aeshraghi@med.miami.edu
authors: Adrien A
authors: AA
authors: Eshraghi
authors: Chhavi
authors: C
authors: Gupta
authors: Thomas R
authors: TR
authors: Van De Water
authors: Jorge E
authors: JE
authors: Bohorquez
authors: Carolyn
authors: C
authors: Garnham
authors: Esperanza
authors: E
authors: Bas
authors: Victoria Maria
authors: VM
authors: Talamo
mesh_terms: D000447:Aldehydes / Q000032:analysis; D000464:Alginates; D000818:Animals; D001309:Auditory Threshold; D053148:Caspase 3 / Q000032:analysis; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D019929:Cochlear Implantation / Q000009:adverse effects*; D004566:Electrodes / Q000009:adverse effects; D016057:Evoked Potentials, Auditory, Brain Stem; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D006820:Hyaluronic Acid; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D009925:Organ of Corti / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000447:Aldehydes; D000464:Alginates; D010455:Peptides; C118495:hyaluronate alginate; D006820:Hyaluronic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; C478085:D-JNKI-1; C027576:4-hydroxy-2-nonenal