title: N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in γ-glutamyl transferase 1 deficient mice.
abstract: 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, Ggt1dwg/dwg, are homozygous for a loss of function mutation of the g-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 Ggt1dwg/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. Ggt1dwg/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.
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Guang-Di
authors.initials: GD
authors.lastname: Chen
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Chantal
authors.initials: C
authors.lastname: Longo-Guess
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Vijaya Prakash Krishnan
authors.initials: VP
authors.lastname: Muthaiah
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Tian
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Sheppard
authors.affiliation: Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Salvi
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D017084:Otoacoustic Emissions, Spontaneous / Q000502:physiology; D011304:Presbycusis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D005723:gamma-Glutamyltransferase / Q000235:genetics*
chemical_list: D005723:gamma-Glutamyltransferase; D000111:Acetylcysteine
keywords: Inner hair cell loss; N-acetyl-L-cysteine; auditory brainstem response; compound action potential; dwarf grey Ggt1dwg/dwg; glutathione; otoacoustic emission; vestibular dysfunction