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

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 15 minutes. Then, 10 mu l of AM-111 at a concentration of 1, 10, or 100 mu M 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 mu M, 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 mu M was more effective than 1 or 10 mu M. 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.