L‐N‐Acetyl‐Cysteine Protection Against Cisplatin‐Induced Auditory Neuronal and Hair Cell Toxicity

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Abstract
The aim of this study is to determine the efficacy of L-N-acetyl-cysteine (L-NAC) as a protectant for inner ear auditory sensory cells against the toxic effects of cisplatin. Prospective laboratory study of the otoprotective effect of L-NAC on auditory neurons and hair cells in vitro. The study has two arms. The first arm evaluated the neuroprotective effect of L-NAC on early postpartum auditory ganglion cell cultures. Two culture media were used. The two media differed in that one of them was enhanced by the addition of neurotrophins (neurotrophin type 3 and brain-derived neurotrophic factor) and a growth factor (transforming growth factor-beta1). Then the survival of cisplatin-treated auditory neurons was studied before and after pretreatment with protective levels of L-NAC. The second arm of the study evaluated the effect of L-NAC on cisplatin damage initiated to auditory hair cells. Early-postpartum organ of Corti explants were grown in culture. Their rate of survival was studied after exposure to toxic levels of cisplatin. Then, survival of cisplatin-damaged hair cells was studied after they were pretreated with L-NAC. Pretreatment of cultures with L-NAC protected both auditory neurons and hair cells from the effects of exposure to toxic levels of cisplatin. This observed otoprotective effect was dose dependent. Our in vitro studies have demonstrated that L-NAC protected both auditory neurons and hair cells from the toxic effects of cisplatin. Because it protects both of these inner ear structures, L-NAC may be potentially useful in protecting hearing, in general, from cisplatin-induced damage. In addition, L-NAC has low systemic and mucosal toxicity. It also has a low molecular weight that may allow it to readily cross the round window membrane. All these characteristics make it potentially suitable for transtympanic application for the prevention of the ototoxicity of cisplatin in vivo.