Tziridis Konstantin, Rasheed Jwan, Kwiatkowska Monika, Wright Matthew, Schlingensiepen Reimar
Experimental Otolaryngology, ENT Clinic Head and Neck Surgery, University Hospital Erlangen, 91054 Erlangen, Germany.
AudioCure Pharma GmbH, 10115 Berlin, Germany.
Int J Mol Sci. 2025 May 27;26(11):5124. doi: 10.3390/ijms26115124.
A single intratympanic application of the small-molecule drug AC102 was previously shown to promote significant recovery of hearing thresholds in a noise-induced hearing loss model in guinea pigs. Here, we report the effects of AC102 to revert synaptopathy of inner hair cells (IHCs) and behavioral signs of tinnitus in Mongolian gerbils following mild noise trauma. This experimental protocol led to minor hearing threshold shifts with no loss of auditory hair cells (HCs) but induced synaptopathy and a sustained and significant tinnitus percept. Treatment by intratympanic application of AC102 was evaluated in two protocols: 1. three weekly injections or 2. a single application. We evaluated hearing threshold changes using the auditory brainstem response (ABR) and the development of a tinnitus percept using the gap prepulse inhibition of acoustic startle (GPIAS) behavioral response. The number of IHC ribbon synapses along the cochlear frequency map were counted by immunostaining for the synaptic ribbon protein carboxy-terminal binding protein 2 (CTBP2). AC102 strongly and significantly reduced behavioral signs of tinnitus, as reflected by altered GPIAS. Noise-induced loss of IHC ribbon synapses was significantly reduced by AC102 compared to vehicle-treated ears. These results demonstrate that a single application of AC102 restores ribbon synapses following mild noise trauma thereby promoting recovery from tinnitus-related behavioral responses in vivo.
此前研究表明，在豚鼠噪声性听力损失模型中，单次鼓室内应用小分子药物AC102可显著促进听力阈值恢复。在此，我们报告了AC102对蒙古沙鼠轻度噪声损伤后内毛细胞（IHC）突触病变及耳鸣行为症状的恢复作用。该实验方案导致听力阈值出现轻微变化，听觉毛细胞（HC）未损失，但诱发了突触病变以及持续且显著的耳鸣感知。通过两种方案评估了鼓室内应用AC102的治疗效果：1. 每周注射三次；2. 单次应用。我们使用听性脑干反应（ABR）评估听力阈值变化，使用惊吓反应的间隙前脉冲抑制（GPIAS）行为反应评估耳鸣感知的发展。通过对突触带状蛋白羧基末端结合蛋白2（CTBP2）进行免疫染色，计数沿耳蜗频率图的IHC带状突触数量。AC102显著且有力地减轻了耳鸣的行为症状，这通过GPIAS的改变得以体现。与载体处理的耳朵相比，AC102显著减少了噪声诱导的IHC带状突触损失。这些结果表明，单次应用AC102可在轻度噪声损伤后恢复带状突触，从而促进体内与耳鸣相关行为反应的恢复。
