Arrest of apoptosis in auditory neurons: Implications for sensorineural preservation in cochlear implantation

Ulysses Scarpidis, Dilip Madnani, Cynthia Shoemaker, Craig H. Fletcher, Ken Kojima, Adrien A. Eshraghi, Hinrich Staecker, Phillipe Lefebvre, Brigitte Malgrange, Thomas J. Balkany, Thomas R. Van De Water

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Hypothesis: The JNK/c-Jun cell death pathway is a major pathway responsible for the loss of oxidative stress-damaged auditory neurons. Background: Implantation of patients with residual hearing accentuates the need to preserve functioning sensorineural elements. Although some auditory function may survive electrode insertion, the probability of initiating an ongoing loss of auditory neurons and hair cells is unknown. Cochlear implantation can potentially generate oxidative stress, which can initiate the cell death of both auditory neurons and hair cells. Methods: Dissociated cell cultures of P4 rat auditory neurons identified the apoptotic pathway initiated by oxidative stress insults (e.g., loss of trophic factor support) and characterized this pathway by arresting translation of pathway-specific mRNA with antisense oligonucleofide treatment and with the use of pathway specific inhibitors. The presence or absence of apoptosis-specific protein and changes in the level of neuronal survival measured the efficacy of these interventional strategies. Results: These in vitro studies identified the JNK/c-Jun cascade as a major initiator of apoptosis of auditory neurons in response to oxidative stress. Neurons pretreated with c-jun antisense oligonucleotide and exposed to high levels of oxidative stress were rescued from apoptosis, whereas neurons in treatment control cultures died. Treatment of oxidative-stressed cultures with either curcumin, a MAPKKK pathway inhibitor, or PD-098059, a MEKI inhibitor, blocked loss of neurons via the JNK/c-Jun apoptotic pathway. Conclusion: Blocking the JNK/c-Jun cell death pathway is a feasible approach to treating oxidative stress-induced apoptosis within the cochlea and may have application as an otoprotective strategy during cochlear implantation.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalOtology and Neurotology
Volume24
Issue number3
DOIs
StatePublished - May 1 2003

Keywords

  • Aptoptosis
  • Auditory neurons
  • c-jun
  • Cochlear implantation
  • Inhibitors
  • Otoprotection
  • Stress kinase pathway

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Neuroscience(all)

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    Scarpidis, U., Madnani, D., Shoemaker, C., Fletcher, C. H., Kojima, K., Eshraghi, A. A., Staecker, H., Lefebvre, P., Malgrange, B., Balkany, T. J., & Van De Water, T. R. (2003). Arrest of apoptosis in auditory neurons: Implications for sensorineural preservation in cochlear implantation. Otology and Neurotology, 24(3), 409-417. https://doi.org/10.1097/00129492-200305000-00011