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Molecular Pharmacology

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Research ArticleArticle

Inhibition of the c-Jun N-Terminal Kinase-Mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-Exposed Animals

Jing Wang, Jérôme Ruel, Sabine Ladrech, Christophe Bonny, Thomas R. van de Water and Jean-Luc Puel
Molecular Pharmacology March 2007, 71 (3) 654-666; DOI: https://doi.org/10.1124/mol.106.028936
Jing Wang
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Jérôme Ruel
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Sabine Ladrech
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Christophe Bonny
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Thomas R. van de Water
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Jean-Luc Puel
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Abstract

We tested and characterized the therapeutic value of round window membrane-delivered (RWM) d-JNKI-1 peptide (Bonny et al., 2001) against sound trauma-induced hearing loss. Morphological characteristics of sound-damaged hair cell nuclei labeled by Hoechst staining show that apoptosis is the predominant mode of cell death after sound trauma. Analysis of the events occurring after sound trauma demonstrates that c-Jun N-terminal kinase (JNK)/stress-activated protein kinase activates a mitochondrial cell death pathway (i.e., activation of Bax, release of cytochrome c, activation of procaspases, and cleavage of fodrin). Fluorescein isothiocyanate (FITC)-conjugated d-JNKI-1 peptide applied onto an intact cochlear RWM diffuses through this membrane and penetrates cochlear tissues with the exception of the stria vascularis. A time sequence of fluorescence measurements demonstrates that FITC-labeled d-JNKI-1 remains in cochlear tissues for as long as 3 weeks. In addition to blocking JNK-mediated activation of a mitochondrial cell death pathway, RWM-delivered d-JNKI-1 prevents hair cell death and development of a permanent shift in hearing threshold that is caused by sound trauma in a dose-dependent manner (EC50 = 2.05 μM). The therapeutic window for protection of the cochlea from sound trauma with RWM delivery of d-JNKI-1 extended out to 12 h after sound exposure. These results show that the mitogen-activated protein kinase/JNK signaling pathway plays a crucial role in sound trauma-initiated hair cell death. Blocking this signaling pathway with RWM delivery of d-JNKI-1 may have significant therapeutic value as a therapeutic intervention to protect the human cochlea from the effects of sound trauma.

Footnotes

  • This work was supported by Auris Medical (contract number 03233A20).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.028936.

  • ABBREVIATIONS: JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; CAP, compound action potential; SEM, scanning electron microscopy; IHC, inner hair cell; OHC, outer hair cell; PTS, permanent threshold shift; HA, hyaluronic acid; RWM, round window membrane; FITC, fluorescein isothiocyanate; AP, artificial perilymph solution; PBS, phosphate-buffered saline; SPL, sound pressure level; RT, room temperature.

    • Received July 18, 2006.
    • Accepted November 21, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Research ArticleArticle

Inhibition of the c-Jun N-Terminal Kinase-Mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-Exposed Animals

Jing Wang, Jérôme Ruel, Sabine Ladrech, Christophe Bonny, Thomas R. van de Water and Jean-Luc Puel
Molecular Pharmacology March 1, 2007, 71 (3) 654-666; DOI: https://doi.org/10.1124/mol.106.028936

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Research ArticleArticle

Inhibition of the c-Jun N-Terminal Kinase-Mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-Exposed Animals

Jing Wang, Jérôme Ruel, Sabine Ladrech, Christophe Bonny, Thomas R. van de Water and Jean-Luc Puel
Molecular Pharmacology March 1, 2007, 71 (3) 654-666; DOI: https://doi.org/10.1124/mol.106.028936
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