Vlajkovic Srdjan M, Chang Hao, Paek Song Yee, Chi Howard H-T, Sreebhavan Sreevalsan, Telang Ravindra S, Tingle Malcolm, Housley Gary D, Thorne Peter R
Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand ; Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Biomed Res Int. 2014;2014:841489. doi: 10.1155/2014/841489. Epub 2014 Aug 26.
We have previously shown that adenosine amine congener (ADAC), a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment.
ADAC (25-300 μg/kg) was administered intraperitoneally to Wistar rats (8-10 weeks old) at intervals (6-72 hours) after exposure to traumatic noise (8-16 kHz, 110 dB sound pressure level, 2 hours). Hearing sensitivity was assessed using auditory brainstem responses (ABR) before and 12 days after noise exposure. Pharmacokinetic studies investigated ADAC concentrations in plasma after systemic (intravenous) administration.
ADAC was most effective in the first 24 hours after noise exposure at doses >50 μg/kg, providing up to 21 dB protection (averaged across 8-28 kHz). Pharmacokinetic studies demonstrated a short (5 min) half-life of ADAC in plasma after intravenous administration without detection of degradation products.
Our data show that ADAC mitigates noise-induced hearing loss in a dose- and time-dependent manner, but further studies are required to establish its translation as a clinical otological treatment.
我们之前已经表明，腺苷胺类似物（ADAC），一种选择性A1腺苷受体激动剂，能够改善噪声和顺铂诱导的耳蜗损伤。在此我们证明了ADAC在大鼠模型中对噪声诱导的耳蜗损伤具有剂量依赖性的挽救作用，并确定了治疗的时间窗。
将Wistar大鼠（8 - 10周龄）暴露于创伤性噪声（8 - 16kHz，110dB声压级，2小时）后，每隔一定时间（6 - 72小时）腹腔注射ADAC（25 - 300μg/kg）。在噪声暴露前和暴露后12天，使用听性脑干反应（ABR）评估听力敏感性。药代动力学研究调查了全身（静脉）给药后血浆中ADAC的浓度。
噪声暴露后最初24小时内，剂量>50μg/kg的ADAC最为有效，可提供高达21dB的保护（8 - 28kHz平均）。药代动力学研究表明，静脉给药后ADAC在血浆中的半衰期较短（5分钟），且未检测到降解产物。
我们的数据表明，ADAC以剂量和时间依赖性方式减轻噪声诱导的听力损失，但需要进一步研究以确定其作为临床耳科治疗方法的转化应用。
