Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity

• Published in: Hearing research 2007-04, Vol.226 (1), p.168-177
• Main Authors: Eshraghi, Adrien A., Wang, Jing, Adil, Eelam, He, Jiao, Zine, Azel, Bublik, Michael, Bonny, Christophe, Puel, Jean-Luc, Balkany, Thomas J., Van De Water, Thomas R.
• Format: Article
• Language: English
• Subjects: Aminoglycoside ototoxicity; Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - toxicity; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Caspases; Caspases - metabolism; D-JNKI-1 peptide (AM-111); Drug toxicity and drugs side effects treatment; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Electrode insertion trauma; Electrodes; Electrodes - adverse effects; Free Radicals; Free Radicals - metabolism; Guinea Pigs; Hair cells; Hearing Loss; Hearing Loss - chemically induced; Hearing Loss - enzymology; Hearing Loss - etiology; Hearing Loss - prevention & control; JNK Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK signaling; Life Sciences; MAP Kinase Signaling System; MAP Kinase Signaling System - drug effects; Medical sciences; Neomycin; Neomycin - toxicity; Neurons and Cognition; Non tumoral diseases; Otoprotection; Otorhinolaryngology. Stomatology; Peptides; Peptides - pharmacology; Pharmacology. Drug treatments; Signal Transduction; Signal Transduction - drug effects; Toxicity: respiratory system, ent, stomatology
• ISSN: 0378-5955; 1878-5891
• DOI: 10.1016/j.heares.2006.09.008

Neomycin ototoxicity and electrode insertion trauma both involve activation of the mitogen activated protein kinase (MAPK)/c-Jun-N-terminal kinase (JNK) cell death signal cascade. This article discusses mechanisms of cell death on a cell biology level (e.g. necrosis and apoptosis) and proposes the blocking of JNK signaling as a therapeutic approach for preventing the development of a permanent hearing loss that can be initiated by either neomycin ototoxicity or electrode insertion trauma. Blocking of JNK molecules incorporates the use of a peptide inhibitor (i.e. D-JNKI-1), which is specific for all three isoforms of JNK and has been demonstrated to prevent loss of hearing following either electrode insertion trauma or loss of both hearing and hair cells following exposure to an ototoxic level of neomycin. We present previously unpublished results that control for the effect of perfusate washout of aminoglycoside antibiotic by perfusion of the scala tympani with an inactive form of D-JNKI-1 peptide, i.e. JNKI-1 mut peptide, which was not presented in the original J. Neurosci. article that tested locally delivered D-JNKI-1 peptide against both noise- and neomycin-induced hearing loss (i.e. Wang, J., Van De Water, T.R., Bonny, C., de Ribaupierre, F., Puel, J.L., Zine, A. 2003a. A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J. Neurosci. 23, 8596–8607). D-JNKI-1 is a cell permeable peptide that blocks JNK signaling at the level of the three JNK molecular isoforms, which when blocked prevents the increases in hearing thresholds and the loss of auditory hair cells. This unique therapeutic approach may have clinical application for preventing: (1) hearing loss caused by neomycin ototoxicity; and (2) the progressive component of electrode insertion trauma-induced hearing loss.