Department of Otorhinolaryngology, ENT Institute, and NHC Key Laboratory of Hearing Medicine, Eye & ENT Hospital, Fudan University, Shanghai, China.
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
FEBS J. 2024 Sep;291(18):4111-4124. doi: 10.1111/febs.17233. Epub 2024 Aug 11.
Afferent synapses between inner hair cells (IHCs) and the type I spiral ganglion neurons (SGNs) in the cochlea provide over 95% of sensory signals for auditory perception in the brain. However, these afferent synapses are particularly vulnerable to damage, for example from excitotoxicity, and exposure to noise in the environment which often leads to noise-induced cochlear synaptopathy (NICS). In this study, we simulated excitotoxic trauma by incubating kainic acid, a non-desensitizing agonist for AMPA type glutamate receptors on cultured cochleae. The possible protective effects of amitriptyline against NICS were examined. We found that, in IHCs, amitriptyline reversed the decrease of Ca current and exocytosis caused by excitotoxic trauma. In SGNs, amitriptyline promoted the recovery of neurite loss caused by excitotoxic trauma. Furthermore, we found that the protective effects of amitriptyline are likely mediated by suppressing apoptosis factors that were upregulated during excitotoxic trauma. In conclusion, our results suggest that amitriptyline could protect afferent synapses in the cochlea from NICS, making it a potential drug candidate for hearing protection.
在耳蜗中，内毛细胞（IHCs）和 I 型螺旋神经节神经元（SGNs）之间的传入突触为大脑提供了超过 95%的听觉感知感觉信号。然而，这些传入突触特别容易受到损伤，例如兴奋性毒性和环境噪声的暴露，这通常会导致噪声诱导的耳蜗突触病（NICS）。在这项研究中，我们通过在培养的耳蜗中孵育海人酸（AMPA 型谷氨酸受体的非脱敏激动剂）来模拟兴奋性毒性损伤。研究了阿米替林对 NICS 的可能保护作用。我们发现，阿米替林可逆转兴奋性毒性损伤引起的 IHCs 钙电流和胞吐减少。在 SGNs 中，阿米替林促进了兴奋性毒性损伤引起的轴突丢失的恢复。此外，我们发现阿米替林的保护作用可能是通过抑制兴奋性毒性损伤期间上调的凋亡因子来介导的。总之，我们的结果表明，阿米替林可以保护耳蜗中的传入突触免受 NICS 的损伤，使其成为一种潜在的听力保护药物候选物。
