Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity.
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 We present previously unpublished results that control for the effect of perfusate washout of aminoglycoside antibiotic by perfusion of the scala tympani with an inactive form of D-JNKI-1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.
Eshraghi
Adrien A
AA
Cochlear Implant Research Program, University of Miami Ear Institute, Department of Otolaryngology, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB 3160, Miami, FL 33136-1015, USA.
Wang
Jing
J
Adil
Eelam
E
He
Jiao
J
Zine
Azel
A
Bublik
Michael
M
Bonny
Christophe
C
Puel
Jean-Luc
JL
Balkany
Thomas J
TJ
Van De Water
Thomas R
TR
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D004566:Electrodes / Q000009:adverse effects; D005609:Free Radicals / Q000378:metabolism; D006168:Guinea Pigs; D034381:Hearing Loss / Q000139:chemically induced / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009355:Neomycin / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000900:Anti-Bacterial Agents; D005609:Free Radicals; D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D009355:Neomycin