Arrest of Apoptosis in Auditory Neurons: Implications for Sensorineural Preservation in Cochlear Implantation

Scarpidis, Ulysses; Madnani, Dilip; Shoemaker, Cynthia; Fletcher, Craig H.; Kojima, Ken; Eshraghi, Adrien A.; Staecker, Hinrich; Pj, Lefèbvre; Malgrange, Brigitte; Bałkany, Thomas J.; Water, Thomas R. Van De

doi:10.1097/00129492-200305000-00011

Cited by 69 publications

(51 citation statements)

References 47 publications

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“…Pretreatment with an antisense oligonucleotide that blocks amplification of c-jun transcription factor, or agents that intervene in the JNK/c-Jun pathway (including curcumin and PD-098059), reduce apoptotic cell death associated with various in vitro insults, including neurotrophin-withdrawal, cisplatin, and exposure to HNE (Scarpidis et al, 2003). Of particular clinical relevance, direct delivery of D-JNKI-1 into the scala tympani eliminated progressive hearing loss in cochleae in which electrodes were inserted to model trauma associated with insertion of a cochlear prosthesis (Van De Water et al, 2005;Eshraghi and Van De Water, 2006).…”

Section: Stress-activated Kinase Activitymentioning

confidence: 99%

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

et al. 2007

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Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7-10 days following noise exposure, and one mechanism underlying noise-induced reduction in cochlear blood flow has finally been identified. These new insights have led to the formulation of new hypotheses regarding the molecular mechanisms of NIHL; and, from these, we have identified interventions that prevent NIHL, even with treatment onset delayed up to 3 days post-noise. It is essential to now assess the additive effects of agents intervening at different points in the cell death pathway to optimize treatment efficacy. Finding safe and effective interventions that attenuate NIHL will provide a compelling scientific rationale to justify human trials to eliminate this single major cause of acquired hearing loss.

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Section: Stress-activated Kinase Activitymentioning

confidence: 99%

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

et al. 2007

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“…Another application in this area is the coating of cochlea implant electrodes with biodegradable carrier substances to release drugs. In this application, glucocorticoids, antioxidants, apoptosis inhibitors or neurotrophins could be employed to counteract side effects of electrode insertion, to aid survival of the spiral ganglia, or to stimulate neurite growth towards the implant electrodes (94).…”

Section: Iii) Biodegradable Biopolymersmentioning

confidence: 99%

Local inner-ear drug delivery and pharmacokinetics

Salt

Plontke

2005

Drug Discovery Today

155

123

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SummaryA number of drugs are in widespread clinical use for the treatment of inner ear disorders by applying them directly to the inner ear. Many new substances and drug delivery systems specific to the inner ear are under development, and in some cases are undergoing evaluations in animal experiments and in clinical studies. The pharmacokinetics of drugs in the inner ear, however, is not well defined and the field is plagued by technical problems in obtaining pure samples of the inner ear fluids for analysis. Nevertheless, a basic understanding of the mechanisms of drug dispersal in the inner ear has emerged that facilitates the design and interpretation of future pharmacokinetic studies.

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“…SGNs critically depend on intact hair cells for continued survival. Following hair cell loss, SGN peripheral processes initially degenerate followed by a gradual loss of the SGNs themselves through apoptosis (Lee et al, 2003, Scarpidis et al, 2003, Ladrech et al, 2004, Alam et al, 2007. Multiple factors that increase SGN survival have been identified, including peptide neurotrophic factors such as neurotrophin-3 (NT-3) and brain derived neurotrophic factors (BDNF) (Staecker et al, 1996, Fritzsch et al, 1997, Mou et al, 1997, Roehm and Hansen, 2005 electrical activity also provides a strong survival stimulus both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

Roehm

Woodson

et al. 2008

Molecular and Cellular Neuroscience

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The effect of membrane electrical activity on spiral ganglion neuron (SGN) neurite growth remains unknown despite its relevance to cochlear implant technology. We demonstrate that membrane depolarization delays the initial formation and inhibits the subsequent extension of cultured SGN neurites. This inhibition depends directly on the level of depolarization with higher levels of depolarization causing retraction of existing neurites. Cultured SGNs express subunits for L-type, N-type, and P/Q type voltage-gated calcium channels (VGCCs) and removal of extracellular Ca 2+ or treatment with a combination of L-type, N-type, P/Q-type VGCC antagonists rescues SGN neurite growth under depolarizing conditions. By measuring the fluorescence intensity of SGNs loaded with the fluorogenic calpain substrate t-butoxy carbonyl-Leu-Met-chloromethylaminocoumarin (20 μM), we demonstrate that depolarization activates calpains. Calpeptin (15 μM), a calpain inhibitor, prevents calpain activation by depolarization and rescues neurite growth in depolarized SGNs suggesting that calpain activation contributes to the inhibition of neurite growth by depolarization. Keywords auditory neuron; axon growth; Ca 2+ /calmodulin dependent kinase II

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Arrest of Apoptosis in Auditory Neurons: Implications for Sensorineural Preservation in Cochlear Implantation

Abstract: 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.

Cited by 69 publications

References 47 publications

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

Local inner-ear drug delivery and pharmacokinetics

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

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