RESUMEN
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.
Asunto(s)
Cóclea/irrigación sanguínea , Pérdida Auditiva/prevención & control , Isquemia/complicaciones , Péptidos/uso terapéutico , Animales , Cóclea/efectos de los fármacos , Cóclea/patología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Gerbillinae , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/patología , Pérdida Auditiva/etiología , Pérdida Auditiva/patología , Isquemia/patología , Péptidos/administración & dosificaciónRESUMEN
Glutamate neurotoxicity in cochlear hair cells was investigated by administering the glutamate agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) into the scala tympani of Mongolian gerbils. AMPA administration caused the formation of large number of vacuoles in the inner hair cells (IHCs) and dendritic terminals. The number of degenerated hair cells was counted using rhodamine-phalloidin and Hoechst 33342 staining. The administration of 50 microM AMPA caused reversible elevation of the auditory brainstem response threshold without loss of IHCs. In contrast, 200 microM AMPA induced a substantial elevation of the auditory brainstem response threshold with the characteristic disappearance of IHCs. As cochlear ischemia involves excessive glutamate release, these results suggest that an elevated glutamate level in the cochlea is responsible for the progressive IHC death related to ischemic injury.