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Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivoThe sensory hair cells of the inner ear undergo apoptosis after acoustic trauma or aminoglycoside antibiotic treatment, causing permanent auditory and vestibular deficits in humans. Previous studies have demonstrated a role for caspase activation in hair cell death and ototoxic injury that can be reduced by concurrent treatment with caspase inhibitors in vitro. In this study, we examined the protective effects of caspase inhibition on hair cell death in vivo after systemic injections of aminoglycosides. In one series of experiments, chickens were implanted with osmotic pumps that administrated the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethylketone (zVAD) into inner ear fluids. One day after the surgery, the animals received a 5 d course of treatment with streptomycin, a vestibulotoxic aminoglycoside. Direct infusion of zVAD into the vestibule significantly increased hair cell survival after streptomycin treatment. A second series of experiments determined whether rescued hair cells could function as sensory receptors. Animals treated with streptomycin displayed vestibular system impairment as measured by a greatly reduced vestibulo-ocular response (VOR). In contrast, animals that received concurrent systemic administration of zVAD with streptomycin had both significantly greater hair cell survival and significantly increased VOR responses, as compared with animals treated with streptomycin alone. These findings suggest that inhibiting the activation of caspases promotes the survival of hair cells and protects against vestibular function deficits after aminoglycoside treatment.
Document ID
20040087601
Document Type
Reprint (Version printed in journal)
Authors
Matsui, Jonathan I.
(Washington University in St. Louis St. Louis, Missouri 63110, United States)
Haque, Asim
Huss, David
Messana, Elizabeth P.
Alosi, Julie A.
Roberson, David W.
Cotanche, Douglas A.
Dickman, J. David
Warchol, Mark E.
Date Acquired
August 21, 2013
Publication Date
July 9, 2003
Publication Information
Publication: The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume: 23
Issue: 14
ISSN: 0270-6474
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: DC03576
CONTRACT_GRANT: F31 DC05082
CONTRACT_GRANT: P30 DC 04665
CONTRACT_GRANT: DC02386
Distribution Limits
Public
Copyright
Other
Keywords
NASA Discipline Neuroscience
Non-NASA Center
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