Rescue of hearing, auditory hair cells, and neurons by CEP-1347/KT7515, an inhibitor 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 ototoxic drug and intense noise trauma. By using phospho-specific c-Jun-N-terminal kinase (JNK) and c-Jun antibodies in immunohistochemistry, we show that the JNK pathway, associated with stress, injury, and apoptosis, is activated in hair cells after trauma. CEP-1347, a derivative of the indolocarbazole K252a, is a small molecule that has been shown to attenuate neurodegeneration by blocking the activation of JNK (). Subcutaneously delivered CEP-1347 attenuated noise-induced hearing loss. The protective effect was demonstrated by functional tests, which showed less hearing threshold shift in CEP-1347-treated than in nontreated guinea pigs, and by morphometric methods showing less hair cell death in CEP-1347-treated cochleas. In organotypic cochlear cultures, CEP-1347 prevented neomycin-induced hair cell death. In addition to hair cells, CEP-1347 promoted survival of dissociated cochlear neurons. These results suggest that therapeutic intervention in the JNK signaling cascade, possibly by using CEP-1347, may offer opportunities to treat inner ear injuries.
Pirvola
U
U
Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland. pirvola@helsinki.fi
Xing-Qun
L
L
Virkkala
J
J
Saarma
M
M
Murakata
C
C
Camoratto
A M
AM
Walton
K M
KM
Ylikoski
J
J
D000617:Aminoglycosides / Q000633:toxicity; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D009355:Neomycin / Q000633:toxicity; D009475:Neurons, Afferent / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009622:Noise / Q000009:adverse effects; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000617:Aminoglycosides; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D016755:Proto-Oncogene Proteins c-jun; C106592:3,9-bis((ethylthio)methyl)-K-252a; D009355:Neomycin