title: Arrest of apoptosis in auditory neurons: implications for sensorineural preservation in cochlear implantation.
abstract: OBJECTIVE
  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 oligonucleotide 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 MEK1 inhibitor, blocked loss of neurons via the JNK/c-Jun apoptotic pathway.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Otolaryngology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ulysses
authors.initials: U
authors.lastname: Scarpidis
authors.forename: Dilip
authors.initials: D
authors.lastname: Madnani
authors.forename: Cynthia
authors.initials: C
authors.lastname: Shoemaker
authors.forename: Craig H
authors.initials: CH
authors.lastname: Fletcher
authors.forename: Ken
authors.initials: K
authors.lastname: Kojima
authors.forename: Adrien A
authors.initials: AA
authors.lastname: Eshraghi
authors.forename: Hinrich
authors.initials: H
authors.lastname: Staecker
authors.forename: Phillipe
authors.initials: P
authors.lastname: Lefebvre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Malgrange
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Balkany
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Van De Water
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D019929:Cochlear Implantation / Q000009:adverse effects*; D003474:Curcumin / Q000008:administration & dosage / Q000009:adverse effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007511:Ischemia / Q000139:chemically induced; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013136:Spiral Ganglion / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D016376:Oligonucleotides, Antisense; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D003474:Curcumin; D002945:Cisplatin