Protection Against Ischemic Cochlear Damage by Intratympanic Administration of AM-111

Otol Neurotol. 2011 Dec;32(9):1422-7. doi: 10.1097/MAO.0b013e3182355658.

Abstract

Objective: AM-111, a cell-permeable peptide inhibitor of c-Jun N-terminal kinase, was investigated for its protective effects against ischemic damage of the cochlea in gerbils.

Methods: Transient cochlear ischemia was introduced in animals by occluding the bilateral vertebral arteries for l5 minutes. Then, 10 μl of AM-111 at a concentration of l, 10, or 100 μM in hyaluronic acid gel formulation was applied onto the round window 30 minutes after the insult. Gel without active substance was used in a control group. Treatment effects were evaluated by auditory brainstem response (ABR) and histology of the inner ear.

Results: In controls, transient cochlear ischemia caused a 25.0 ± 5.0 dB increase in the ABR threshold at 8 kHz and a decrease of 13.3 ± 2.3% in inner hair cells at the basal turn on Day 7. Ischemic damage was mild at 2 and 4 kHz. When the animals were treated with AM-111 at 100 μM, cochlear damage was significantly reduced: the increase in ABR threshold was 3.3 ± 2.4 dB at 8 kHz, and the inner hair cell loss was 3.1 ± 0.6% at the basal turn on Day 7. The effects of AM-111 were concentration dependent: 100 μM was more effective than 1 or 10 μM.

Conclusion: Direct application of AM-111 in gel formulation on the round window was effective in preventing acute hearing loss because of transient cochlear ischemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cochlea / blood supply*
  • Cochlea / drug effects
  • Cochlea / pathology
  • Evoked Potentials, Auditory, Brain Stem / drug effects
  • Gerbillinae
  • Hair Cells, Auditory / drug effects
  • Hair Cells, Auditory / pathology
  • Hearing Loss / etiology
  • Hearing Loss / pathology
  • Hearing Loss / prevention & control*
  • Ischemia / complications*
  • Ischemia / pathology
  • Peptides / administration & dosage
  • Peptides / therapeutic use*

Substances

  • Peptides
  • D-JNKI-1