Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand.
Exp Gerontol. 2011 Nov;46(11):905-14. doi: 10.1016/j.exger.2011.08.001. Epub 2011 Aug 7.
This study was undertaken to determine the role of adenosine signalling in the development of age-related hearing loss (ARHL). We and others have shown previously that adenosine signalling via A(1) receptors is involved in cochlear protection from noise-induced cochlear injury. Here we demonstrate that enhanced adenosine signalling in the cochlea provides partial protection from ARHL in C57BL/6J mice. We targeted adenosine kinase (ADK), the key enzyme in adenosine metabolism, using a treatment regime with the selective ADK inhibitor ABT-702 (1.5mg/kg intraperitoneally twice a week) commencing at the age of three months or six months. This treatment, intended to increase free adenosine levels in the cochlea, was maintained until the age of nine months and hearing thresholds were evaluated monthly using auditory brainstem responses (ABR). At nine months, when C57BL/6J mice normally exhibit significant ARHL, both groups treated with ABT-702 showed lower ABR threshold shifts at 10 and 16kHz compared to control animals receiving the vehicle solution. The better thresholds of the ABT-702-treated mice at these frequencies were supported by increased survival of hair cells in the apical region of the cochlea. This study provides the first evidence that ARHL can be mitigated by enhancing adenosine signalling in the cochlea.
这项研究旨在确定腺苷信号在年龄相关性听力损失（ARHL）发展中的作用。我们和其他人之前已经表明，通过 A1 受体的腺苷信号参与了耳蜗对噪声引起的耳蜗损伤的保护。在这里，我们证明耳蜗中增强的腺苷信号为 C57BL/6J 小鼠的 ARHL 提供了部分保护。我们使用选择性 ADK 抑制剂 ABT-702（1.5mg/kg 腹腔内每周两次）的治疗方案靶向腺苷激酶（ADK），该酶是腺苷代谢的关键酶，该治疗方案从三个月或六个月大开始。这种旨在增加耳蜗中游离腺苷水平的治疗方法一直持续到九个月大，并且使用听觉脑干反应（ABR）每月评估听力阈值。在九个月大时，C57BL/6J 小鼠通常会出现明显的 ARHL，与接受载体溶液的对照动物相比，用 ABT-702 治疗的两组在 10 和 16kHz 时 ABR 阈值的变化都较低。ABR 治疗组在这些频率下的更好阈值得到了耳蜗顶部区域毛细胞存活增加的支持。这项研究首次提供了证据，表明通过增强耳蜗中的腺苷信号可以减轻 ARHL。
