D-methionine administered as late as 36 hours post-noise exposure rescues from permanent threshold shift and dose-dependently increases serum antioxidant levels

To elucidate D-methionine’s (D-met) dose and time rescue parameters from steady-state or impulse noise-induced permanent threshold shift (PTS) and determine D-met rescue’s influence on serum and cochlear antioxidant levels. Five D-met doses at 0, 50, 100, or 200 mg/kg/dose administered starting at 1, 24, or 36 hours post steady-state or impulse noise exposure. Auditory brainstem responses at baseline and 21 days post-noise measured PTS. Serum (superoxide dismutase [SOD], catalase [CAT],, glutathione reductaseand glutathione peroxidase [GPx]) and cochlear (Glutathione [GSH] and glutathione disulphide [GSSG]) antioxidant levels measured physiological impact. <i>Chinchillas</i> (10/study group; 6–8/confirmatory groups). D-met significantly reduced PTS for impulse noise (100 mg [2, 6, 14 and 20 kHz]; 200 mg [2, 14 and 20 kHz]) and steady-state noise (all dosing groups, time parameters and tested frequencies). PTS reduction did not significantly vary by rescue time. D-met significantly increased serum SOD (100 and 200 mg for 24 hour rescue) and GPx (50 mg/kg at 24 hour rescue) at 21 days post-noise. Cochlear GSH and GSSG levels were unaffected relative to control. D-met rescues from steady-state and impulse noise-induced PTS even when administered up to 36 hours post-noise and dose-dependently influences serum antioxidant levels even 21 days post-noise. D-met’s broad and effective dose/time window renders it a promising antioxidant rescue agent.

本研究旨在阐明D-甲硫氨酸（D-methionine, D-met）对稳态噪声或脉冲噪声诱导的永久性阈移（permanent threshold shift, PTS）的挽救剂量与时间参数，并明确D-甲硫氨酸挽救治疗对血清及耳蜗抗氧化水平的影响。实验设置5种D-甲硫氨酸给药剂量（0、50、100、200 mg/剂），于稳态噪声或脉冲噪声暴露后1、24、36小时启动给药。分别于基线及噪声暴露后21天检测听性脑干反应（auditory brainstem responses, ABR）以评估永久性阈移。通过检测血清抗氧化指标[超氧化物歧化酶（superoxide dismutase, SOD）、过氧化氢酶（catalase, CAT）、谷胱甘肽还原酶及谷胱甘肽过氧化物酶（glutathione peroxidase, GPx）]与耳蜗抗氧化指标[谷胱甘肽（glutathione, GSH）及氧化型谷胱甘肽（glutathione disulphide, GSSG）]，评估其生理效应。实验动物为毛丝鼠（Chinchilla），每组10只（实验组），验证组每组6~8只。

实验结果显示：D-甲硫氨酸可显著降低脉冲噪声诱导的永久性阈移（100 mg剂量组对应2、6、14及20 kHz频率；200 mg剂量组对应2、14及20 kHz频率），同时可显著改善所有给药组、时间参数及测试频率下稳态噪声诱导的永久性阈移。挽救给药的时间对永久性阈移的改善效果无显著差异。噪声暴露后21天检测结果表明，D-甲硫氨酸可显著提升血清SOD水平（24小时挽救给药的100及200 mg剂量组）与GPx水平（24小时挽救给药的50 mg/kg剂量组）。耳蜗GSH与GSSG水平与对照组相比无显著变化。

研究结论：即使于噪声暴露后36小时给药，D-甲硫氨酸仍可挽救稳态噪声及脉冲噪声诱导的永久性阈移，且可在噪声暴露后21天仍呈现剂量依赖性的血清抗氧化水平调控作用。D-甲硫氨酸具备宽泛且高效的给药剂量与时间窗口，是一种极具应用前景的抗氧化挽救制剂。