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Blockade of c-Jun N-terminal kinase pathway attenuates gentamicin-induced cochlear and vestibular hair cell death
Jukka Ylikoski1, Liang Xing-Qun, Jussi Virkkala
1Institute of Biotechnology, University of Helsinki, Finland. jukka.ylikoski@helsinki.fi
Abstract:
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.
Insights
Gentamicin causes inner ear hair cell death via JNK activation. Inhibiting this pathway with CEP-1347 protects against hearing loss and hair cell damage from gentamicin and noise.
Area of Science:
- Ototoxicity
- Neuroscience
- Cell Biology
Background:
- Aminoglycoside antibiotics like gentamicin cause inner ear hair cell loss, but molecular mechanisms remain unclear.
- Previous studies linked neomycin-induced ototoxicity to c-Jun N-terminal kinase (JNK) pathway activation in cochlear cultures.
- CEP-1347, a JNK inhibitor, previously attenuated hair cell death in vitro.
Purpose of the Study:
- To investigate the role of JNK activation in gentamicin-induced ototoxicity in vivo.
- To evaluate the protective effects of CEP-1347 against gentamicin-induced hearing loss and hair cell damage.
- To explore JNK activation as a common pathway in inner ear sensory cell stress.
Main Methods:
- In vivo study of gentamicin-induced ototoxicity in animal models.
- Assessment of JNK pathway activation in inner ear hair cells following gentamicin exposure.
- Administration of CEP-1347 to evaluate its efficacy in preventing hair cell loss and auditory deficits.
- Histological analysis of cochlear and vestibular hair cell survival.
Main Results:
- Gentamicin exposure activated the JNK pathway and induced apoptosis in inner ear hair cells in vivo.
- Systemic administration of CEP-1347 significantly attenuated gentamicin-induced hearing sensitivity loss.
- CEP-1347 treatment reduced hair cell damage in the cochlea and vestibular organs, particularly protecting inner hair cells and type I vestibular hair cells.
- These findings align with previous results showing CEP-1347 protects against noise-induced hair cell loss.
Conclusions:
- JNK pathway activation is a key molecular event in gentamicin-induced ototoxicity.
- Inhibiting JNK signaling with CEP-1347 offers a potential therapeutic strategy to prevent aminoglycoside-induced hearing and vestibular damage.
- JNK activation may represent a common mechanism underlying sensory cell stress and death in the inner ear from various insults.
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