Rescue of hearing, auditory hair cells, and neurons by CEP-1347/KT7515, aninhibitor of c-Jun N-terminal kinase activation

We have studied the mechanisms of auditory hair cell death after insults in vitro and in vivo. We show DNA fragmentation of hair cell nuclei after oto toxic drug and intense noise trauma. By using phospho-specific c-Jun-N-term inal kinase (JNK) and c-Jun antibodies in immunohistochemistry, we show tha t the JNK pathway, associated with stress, injury, and apoptosis, is activa ted in hair cells after trauma. CEP-1347, a derivative of the indolocarbazo le K252a, is a small molecule that has been shown to attenuate neurodegener ation by blocking the activation of JNK (Maroney et al., 1998). Subcutaneou sly delivered CEP-1347 attenuated noise-induced hearing loss. The protectiv e effect was demonstrated by functional tests, which showed less hearing th reshold shift in CEP-1347-treated than in nontreated guinea pigs, and by mo rphometric methods showing less hair cell death in CEP-1347-treated cochlea s. In organotypic cochlear cultures, CEP-1347 prevented neomycin-induced ha ir cell death. In addition to hair cells, CEP-1347 promoted survival of dis sociated cochlear neurons. These results suggest that therapeutic intervent ion in the JNK signaling cascade, possibly by using CEP-1347, may offer opp ortunities to treat inner ear injuries.