Blockade of c-Jun N-terminal kinase pathway attenuates gentamicin-induced cochlear and vestibular hair cell death.
The ototoxic action of aminoglycoside antibiotics leading to the loss of inner ear hair cells is well documented. However, the molecular mechanisms are poorly defined. We have previously shown that in neomycin-exposed cochlear organotypic cultures, the c-Jun N-terminal kinase (JNK) pathway - associated with stress, injury and apoptosis - is activated in hair cells. We have shown that hair cell death can be attenuated by CEP-1347, an inhibitor of JNK signaling (). In the present study, we demonstrate that gentamicin-induced ototoxicity leads to JNK activation and apoptosis in the inner ear hair cells in vivo. We show that systemic administration of CEP-1347 attenuates gentamicin-induced decrease of auditory sensitivity and cochlear hair cell damage. In addition, CEP-1347 treatment reduces the extent of hair cell loss in the ampullary cristae after gentamicin intoxication. Particularly, the inner hair cells of the cochlea and type I hair cells of the vestibular organs are protected. Our previous data have shown that also acoustic overstimulation can cause apoptotic death of cochlear hair cells and that CEP-1347 can attenuate noise-induced hair cell loss. Thus, our results imply that activation of JNK cascade may be a common molecular outcome of cellular stress in the inner ear sensory epithelia and that attenuation of the lesion can be provided by inhibiting JNK activation.
Ylikoski
Jukka
J
Institute of Biotechnology, University of Helsinki, Finland. jukka.ylikoski@helsinki.fi
Xing-Qun
Liang
L
Virkkala
Jussi
J
Pirvola
Ulla
U
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001309:Auditory Threshold / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D003051:Cochlea / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005839:Gentamicins / Q000633:toxicity*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018069:Hair Cells, Vestibular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005839:Gentamicins; D007211:Indoles; C106592:3,9-bis((ethylthio)methyl)-K-252a; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases