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PMID: 10627579 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 20 ·No. 1 ·2000-01-01 ·Pages 43-50

Pirvola U, Xing-Qun L, Virkkala J, Saarma M, Murakata C, Camoratto AM, Walton KM, Ylikoski J

Abstract

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.

MeSH Terms
Aminoglycosides/toxicity Animals Carbazoles/pharmacology Cell Death/drug effects Cell Survival/drug effects Cells, Cultured Enzyme Activation/drug effects Enzyme Inhibitors/pharmacology Hair Cells, Auditory/cytology,drug effects,physiology Hearing Loss, Noise-Induced/chemically induced,drug therapy,pathology Indoles/pharmacology Neomycin/toxicity Neurons, Afferent/cytology,drug effects,physiology Noise/adverse effects Proto-Oncogene Proteins c-jun/antagonists & inhibitors,metabolism Rats Rats, Wistar Signal Transduction/drug effects,physiology
Chemicals
Aminoglycosides Carbazoles Enzyme Inhibitors Indoles Proto-Oncogene Proteins c-jun 3,9-bis((ethylthio)methyl)-K-252a Neomycin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Pirvola U
Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland. pirvola@helsinki.fi
Xing-Qun L
Virkkala J
Saarma M
Murakata C
Camoratto A M
Walton K M
Ylikoski J
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Email
pirvola@helsinki.fi
Published
2000-01-01
Pages
43-50
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6774096
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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