Fang Jia, Li Zhuangzhuang, Wang Pengjun, Zhang Xiaoxu, Mao Song, Li Yini, Yu Dongzhen, Li Xiaoyan, Xing Yazhi, Shi Haibo, Yin Shankai
Department of Otolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Otolaryngology Institute of Shanghai Jiao Tong University; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
Department of Otorhinolaryngology-Head and Neck Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Neural Regen Res. 2025 Oct 1;20(10):3025-3039. doi: 10.4103/NRR.NRR-D-23-01879. Epub 2024 Jun 3.
JOURNAL/nrgr/04.03/01300535-202510000-00031/figure1/v/2024-11-26T163120Z/r/image-tiff Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum. However, their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target. In addition, the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure. To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides, we used a C57BL/6J mouse model treated with kanamycin. We found that the mice exhibited auditory deficits following the acute loss of outer hair cells. Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time. Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response, particularly those related to the NLRP3 inflammasome. Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed, accompanied by infiltration of macrophages and the release of proinflammatory cytokines. Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model. These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration. Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.
《期刊》/nrgr/04.03/01300535 - 202510000 - 00031/图1/v/2024 - 11 - 26T163120Z/图像 - tiff 氨基糖苷类是一类广泛使用的抗菌药物，以其有效性和广泛的抗菌谱而闻名。然而，它们的使用会导致毛细胞凋亡，直接靶向导致不可逆转的听力损伤。此外，氨基糖苷类引起的听力损伤在暴露时涉及螺旋神经节神经元的损伤。为了研究氨基糖苷类诱导螺旋神经节神经元变性的机制，我们使用了卡那霉素处理的C57BL/6J小鼠模型。我们发现，小鼠在外毛细胞急性丧失后出现听觉缺陷。螺旋神经节神经元表现出焦亡的特征，并随时间逐渐变性。对这些神经元的转录组分析显示，与炎症和免疫反应相关的基因显著上调，特别是那些与NLRP3炎性小体相关的基因。观察到螺旋神经节神经元中经典焦亡途径的激活，伴有巨噬细胞浸润和促炎细胞因子的释放。使用Mcc950靶向NLRP3的药物干预和使用NLRP3基因敲除的基因干预改善了损伤模型中螺旋神经节神经元的变性。这些发现表明，NLRP3炎性小体介导的焦亡在氨基糖苷类诱导的螺旋神经节神经元变性中起作用。抑制该途径可能为通过减少螺旋神经节神经元变性来治疗感音神经性听力损失提供一种潜在的治疗策略。
