Amitriptyline protects afferent synapses in the cochlea against excitotoxic trauma in vitro

• Published in: The FEBS journal Vol. 291; no. 18; pp. 4111 - 4124
• Main Authors: Wang, Liqin, Xu, Mengfan, Zhang, Qing, Li, Geng‐Lin
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2024
• Subjects: afferent synapses; Amitriptyline; Apoptosis; Auditory perception; Brain damage; Brain injury; Ca2+ current; Calcium currents; Calcium ions; Cochlea; cochlear synaptopathy; Desensitization; Drug development; Ear protection; excitotoxic trauma; Excitotoxicity; Exocytosis; Glutamate receptors; Hair cells; Hearing protection; Kainic acid; Noise; Noise levels; Sensory neurons; Spiral ganglion; Synapses; Trauma; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; amitriptyline; exocytosis; cochlear synaptopathy; excitotoxic trauma; afferent synapses; Ca2+ current
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17233

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 Ca2+ 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. Kainic acid (KA) leads to damage in cochlear synapses, as well as resulting in decreased Ca2+ currents and exocytosis in inner hair cells (IHCs). Amitriptyline, a tricyclic antidepressant, exerts a protective effect by reversing these detrimental changes providing protection. It restores Ca2+ current and exocytosis in IHCs and promotes nerve fiber recovery in spiral ganglion neurons, both affected by KA. Amitriptyline could protect cochlear afferent synapses from KA, suggesting its potential as a hearing protection drug.