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, Jean Luc Puel

Research output: Contribution to journalArticle

83 Citations (Scopus)

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 (EC 50 = 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.

Original languageEnglish
Pages (from-to)654-666
Number of pages13
JournalMolecular Pharmacology
Volume71
Issue number3
DOIs
StatePublished - Mar 1 2007

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Auditory Pathways
JNK Mitogen-Activated Protein Kinases
Cell Death
Cochlea
Wounds and Injuries
Membranes
Fluorescein
Ear Round Window
Stria Vascularis
Inhibition (Psychology)
Peptides
Therapeutics
Heat-Shock Proteins
Cytochromes c
Mitogen-Activated Protein Kinases
Cell Nucleus
Hearing Loss
Protein Kinases
Hearing
D-JNKI-1

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of the c-Jun N-terminal kinase-mediated mitochondrial cell death pathway restores auditory function in sound-exposed animals. / Wang, Jing; Ruel, Jérôme; Ladrech, Sabine; Bonny, Christophe; Van De Water, Thomas R; Puel, Jean Luc.

In: Molecular Pharmacology, Vol. 71, No. 3, 01.03.2007, p. 654-666.

Research output: Contribution to journalArticle

Wang, Jing ; Ruel, Jérôme ; Ladrech, Sabine ; Bonny, Christophe ; Van De Water, Thomas R ; Puel, Jean Luc. / Inhibition of the c-Jun N-terminal kinase-mediated mitochondrial cell death pathway restores auditory function in sound-exposed animals. In: Molecular Pharmacology. 2007 ; Vol. 71, No. 3. pp. 654-666.
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