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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 hair cells of the inner ear is well documented. However, the molecular mechanisms are poorly defined. We have previously shown that in neomycin-exposed organotypic cultures of the cochlea, the c-Jun N-terminal kinase (JNK) pathway--associated with stress, injury and apoptosis--is activated in hair cells and leads to their death. We have also shown that hair cell death can be attenuated by CEP-1347, an inhibitor of JNK signalling [Pirvola et al., J. Neurosci. 20 (2000) 43-50]. 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 also 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. We have previously shown that also acoustic overstimulation leads to apoptosis of cochlear hair cells and that CEP-1347 can attenuate noise-induced sensory cell loss. These results suggest that activation of the 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 ototoxicity activates the c-Jun N-terminal kinase (JNK) pathway, causing inner ear hair cell death. Inhibiting JNK with CEP-1347 protects against gentamicin-induced hearing loss and hair cell damage.
Area of Science:
- Ototoxicity and Inner Ear Physiology
- Molecular Mechanisms of Apoptosis
- Neuroscience and Pharmacology
Background:
- Aminoglycoside antibiotics like gentamicin cause ototoxicity, leading to inner ear hair cell loss.
- The precise molecular mechanisms underlying aminoglycoside-induced ototoxicity remain poorly understood.
- Previous research implicated the c-Jun N-terminal kinase (JNK) pathway in neomycin-induced hair cell death.
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, a JNK inhibitor, against gentamicin-induced ototoxicity.
- To determine if JNK activation is a common pathway for 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 hearing loss and hair cell damage.
- Histological analysis of cochlear and vestibular hair cell survival.
Main Results:
- Gentamicin administration 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 loss in both cochlear and vestibular organs.
- Inner hair cells and type I vestibular hair cells showed particular protection.
Conclusions:
- JNK pathway activation is a key molecular event in gentamicin-induced ototoxicity.
- Inhibition of 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 of cellular stress and apoptosis in inner ear sensory epithelia, suggesting broader therapeutic potential for JNK inhibitors.
