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The Journal of Neuroscience, September 17, 2003, 23(24):8596-8607

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A Peptide Inhibitor of c-Jun N-Terminal Kinase Protects against Both Aminoglycoside and Acoustic Trauma-Induced Auditory Hair Cell Death and Hearing Loss

J. Wang,¹ T. R. Van De Water,² C. Bonny,³ F. de Ribaupierre,⁴ J. L. Puel,¹ and A. Zine^1,4

¹Institut National de la Santé et de la Recherche Médicale U583, Physiopathologie et Thérapie des Déficits Sensoriels et Moteurs, Université de Montpellier I, 34090 Montpellier, France, ²Cochlear Implant Research Program, University of Miami Ear Institute, Miami, Florida 33136, ³Division de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland, and ⁴ Institut de Physiologie, Université de Lausanne, 1005 Lausanne, Switzerland

Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK).

We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK–JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK–JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK–JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

Key words: neomycin; ototoxicity; acoustic trauma; noise-induced hearing loss; apoptosis of hair cells; c-Jun N-terminal kinase (JNK); JNK inhibition; organ of Corti

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Received April 17, 2003; revised July 7, 2003; accepted July 15, 2003.

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