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

• DOI: 10.1124/mol.106.028936
• Publication Date: 2006-11-29T03:04:08Z
• Authors: Jing Wang; Jérôme Ruel; Sabine Ladrech; Christophe Bonny; Thomas R. van de ...; Jean-Luc Puel
• Keywords: c-jun

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