Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, Auckland 1142, New Zealand.
Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, Auckland 1023, New Zealand.
Int J Mol Sci. 2021 Jul 27;22(15):8000. doi: 10.3390/ijms22158000.
Age-related hearing loss (ARHL) is the most common sensory disorder among older people, and yet, the treatment options are limited to medical devices such as hearing aids and cochlear implants. The high prevalence of ARHL mandates the development of treatment strategies that can prevent or rescue age-related cochlear degeneration. In this study, we investigated a novel pharmacological strategy based on inhibition of the adenosine A receptor (AR) in middle aged C57BL/6 mice prone to early onset ARHL. C57BL/6J mice were treated with weekly istradefylline (AR antagonist; 1 mg/kg) injections from 6 to 12 months of age. Auditory function was assessed using auditory brainstem responses (ABR) to tone pips (4-32 kHz). ABR thresholds and suprathreshold responses (wave I amplitudes and latencies) were evaluated at 6, 9, and 12 months of age. Functional outcomes were correlated with quantitative histological assessments of sensory hair cells. Cognitive function was assessed using the Morris water maze and the novel object recognition test, and the zero maze test was used to assess anxiety-like behaviour. Weekly injections of istradefylline attenuated ABR threshold shifts by approximately 20 dB at mid to high frequencies (16-32 kHz) but did not improve ABR suprathreshold responses. Istradefylline treatment improved hair cell survival in a turn-dependent manner, whilst the cognitive function was unaffected by istradefylline treatment. This study presents the first evidence for the rescue potential of istradefylline in ARHL and highlights the role of AR in development of age-related cochlear degeneration.
年龄相关性听力损失（ARHL）是老年人中最常见的感觉障碍，但治疗选择仅限于助听器和人工耳蜗等医疗设备。ARHL 的高患病率要求开发能够预防或挽救与年龄相关的耳蜗退化的治疗策略。在这项研究中，我们研究了一种基于抑制中年 C57BL/6 小鼠中腺苷 A 受体（AR）的新型药物策略，这些小鼠易发生早期 ARHL。从 6 到 12 个月大，C57BL/6J 小鼠每周接受异丁司特茶碱（AR 拮抗剂；1mg/kg）注射。使用听觉脑干反应（ABR）对音调（4-32 kHz）评估听觉功能。在 6、9 和 12 个月大时评估 ABR 阈值和阈上反应（波 I 幅度和潜伏期）。功能结果与感觉毛细胞的定量组织学评估相关。使用 Morris 水迷宫和新物体识别测试评估认知功能，使用零迷宫测试评估焦虑样行为。每周注射异丁司特茶碱可使中高频（16-32 kHz）的 ABR 阈值移位降低约 20 dB，但不能改善 ABR 阈上反应。异丁司特茶碱治疗以转弯依赖的方式改善毛细胞存活，而认知功能不受异丁司特茶碱治疗的影响。这项研究首次提供了异丁司特茶碱在 ARHL 中具有挽救潜力的证据，并强调了 AR 在与年龄相关的耳蜗退化发展中的作用。
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