N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in γ-glutamyl transferase 1 deficient mice.
N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in γ-glutamyl transferase 1 deficient mice.
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DOI：
10.18632/aging.100927
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发表时间：
2016-04
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影响因子：
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通讯作者：
Johnson KR
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文献类型：
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作者：
Ding D;Jiang H;Chen GD;Longo-Guess C;Muthaiah VP;Tian C;Sheppard A;Salvi R;Johnson KR
年龄相关性听力损失（ARHL）是老年人最常见的疾病之一，遗传因素和氧化应激是其主要决定因素。矮灰小鼠（Ggt 1dwg/dwg）是γ-谷氨酰转移酶1基因功能缺失突变的纯合子，该基因编码一种重要的抗氧化酶，对谷胱甘肽（GSH）的再合成至关重要。由于GSH减少氧化损伤，我们假设Ggt 1dwg/dwg小鼠对ARHL易感。令人惊讶的是，耳声发射和耳蜗微音器电位，反映耳蜗外毛细胞（OHC）的功能，在很大程度上不受影响的突变小鼠，而听觉脑干反应和复合动作电位严重异常。这些功能缺陷与内毛细胞（IHC）的不寻常和选择性损失有关，但保留OHC和听神经纤维。值得注意的是，听力障碍和IHC损失完全防止N-乙酰-L-半胱氨酸，诱导从头合成的谷胱甘肽;然而，听力障碍和IHC损失再次出现时，治疗停止。Ggt 1dwg/dwg小鼠代表了一种重要的新模型，用于研究ARHL，治疗干预措施，并了解由专门来自IHC的感觉输入损失引起的感觉剥夺的感知和电生理后果。
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 γ-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/dwgmice 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.