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

Laryngoscope. 2013 Mar;123 Suppl 1:S1-14. doi: 10.1002/lary.23902. Epub 2013 Feb 4.

Abstract

Objectives/hypothesis: To investigate the molecular mechanisms involved in electrode insertion trauma (EIT) and to test the otoprotective effect of locally delivered AM-111.

Study design: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / analysis
  • Alginates
  • Animals
  • Auditory Threshold
  • Caspase 3 / analysis
  • Cell Count
  • Cell Death / physiology
  • Cochlear Implantation / adverse effects*
  • Electrodes / adverse effects
  • Evoked Potentials, Auditory, Brain Stem
  • Guinea Pigs
  • Hair Cells, Auditory / cytology
  • Hair Cells, Auditory / drug effects*
  • Hair Cells, Auditory / physiology*
  • Hyaluronic Acid
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / physiology*
  • Organ of Corti / drug effects
  • Peptides / pharmacology*
  • Signal Transduction*

Substances

  • Aldehydes
  • Alginates
  • Peptides
  • hyaluronate alginate
  • Hyaluronic Acid
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 3
  • D-JNKI-1
  • 4-hydroxy-2-nonenal