期刊
AGING-US
卷 8, 期 4, 页码 730-750出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100927
关键词
Inner hair cell loss; dwarf grey Ggt1(dwg/dwg); otoacoustic emission; compound action potential; vestibular dysfunction; auditory brainstem response; glutathione; N-acetyl-L-cysteine
资金
- National Institutes of Health (NIH) [R01DC005827]
Genetic factors combined with oxidative stress are major determinants of age-related hearing loss (ARHL), one of the most prevalent disorders of the elderly. Dwarf grey mice, Ggt1(dwg/dwg), are homozygous for a loss of function mutation of the gamma-glutamyl transferase 1 gene, which encodes an important antioxidant enzyme critical for the resynthesis of glutathione (GSH). Since GSH reduces oxidative damage, we hypothesized that Ggt1(dwg/dwg) mice would be susceptible to ARHL. Surprisingly, otoacoustic emissions and cochlear microphonic potentials, which reflect cochlear outer hair cell (OHC) function, were largely unaffected in mutant mice, whereas auditory brainstem responses and the compound action potential were grossly abnormal. These functional deficits were associated with an unusual and selective loss of inner hair cells (IHC), but retention of OHC and auditory nerve fibers. Remarkably, hearing deficits and IHC loss were completely prevented by N-acetyl-L-cysteine, which induces de novo synthesis of GSH; however, hearing deficits and IHC loss reappeared when treatment was discontinued. Ggt1(dwg/dwg) mice represent an important new model for investigating ARHL, therapeutic interventions, and understanding the perceptual and electrophysiological consequences of sensory deprivation caused by the loss of sensory input exclusively from IHC.
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