中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (5): 1483-1494.doi: 10.4103/NRR.NRR-D-24-00130

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

反苯环丙胺减轻NOD样受体热蛋白结构域相关蛋白3相关噪声诱导的听力损失

  

  • 出版日期:2025-05-15 发布日期:2024-10-31
  • 基金资助:
    国家重点研发计划（2022YFC2402701）、国家自然科学基金国际（地区）合作与交流项目（81820108009）、面上项目（81970890、82371148）等。

Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

Xihang Chen1, 2, 3, 4, 5, 6, # , Zhifeng Chen1, 2, 3, 4, 5, 7, # , Menghua Li 1, 2, 3, 4, 5, # , Weiwei Guo1, 2, 3, 4, 5, # , Shuolong Yuan1, 2, 3, 4, 5 , Liangwei Xu1, 2, 3, 4, 5 , Chang Lin6, * , Xi Shi 8, 9, * , Wei Chen1, 2, 3, 4, 5, * , Shiming Yang1, 2, 3, 4, 5, *   

  1. 1 Senior Department of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China;   2 State Key Laboratory of Hearing and Balance Science, Beijing, China;   3 Nattonal Clinical Research Center for Otolaryngologic Diseases, Beijing, China;   4 Key Laboratory of Hearing Science, Ministry of Educatton, Beijing, China;   5 Beijing Key Laboratory of Hearing Impairment Preventton and Treatment, Beijing, China;   6 Department of Otorhinolaryngology Head and Neck Surgery, The First Afffliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China;   7 Department of Otolaryngology Head and Neck Surgery, The 940th Hospital of Joint Logisttcs Support Force of Chinese PLA, Lanzhou, Gansu Province, China;   8 Key Laboratory of Tropical Biological Resources of Ministry of Educatton, School of Pharmaceuttcal Sciences, Hainan University, Haikou, Hainan Province, China;   9 Academician Workstatton of Hainan University, School of Pharmaceuttcal Sciences, Yazhou Bay, Sanya, Hainan Province, China
  • Online:2025-05-15 Published:2024-10-31
  • Contact: Shiming Yang, PhD, MD, shm_yang@163.com; Wei Chen, PhD, MD, chenwe301@sina.com; Xi Shi, PhD, 100002013036@xzhmu.edu.cn; Chang Lin, PhD, MD, linc301@sina.com.
  • Supported by:
    This work was supported by the Nattonal Key Research and Development Program of China, No. 2022YFC2402701 (to WC); Key Internattonal (Regional) Joint Research Program of the Nattonal Natural Science Foundatton of China, No. 81820108009 (to SY); the Nattonal Natural Science Foundatton of China, Nos. 81970890 (to WC) and 82371148 (to WG); Fujian Provincial Healthcare Young and Middle-aged Backbone Talent Training Project, No. 2023GGA035 (to XC); Spring City Plan, the High-level Talent Promotton and Training Project of Kunming, No. 2022SCP001 (to SY); the Natural Science Foundatton of Hainan Province of China, No. 824MS052 (to XS); and the Sixth Medical Center of Chinese PLA General Hospital Innovatton Culttvatton, No. CXPY202116 (to LX).

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摘要：

噪声介导听力损伤是除遗传因素外，导致听功能异常的最主要诱因之一；然而目前尚无任何药物干预措施，主要原因在于其相关机制不清，治疗靶点不明所致。为此，实验利用120dB SPL的宽频白噪声建立小鼠噪声损伤模型，听性脑干诱发电位和畸变产物耳声发射结果显示，暴露4h白噪声能引起小鼠永久性阈移。随即进行小分子药物反苯环丙胺干预，在噪声暴露后第4天，反苯环丙胺表现出较好的听觉保护作用。在噪声暴露后第14天，反苯环丙胺对click、4 kHz、8 kHz和16 kHz等不同频率均表现为显著性保护效果。扫描电镜等形态学数据进一步佐证了上述结论。分子层面发现，治疗后导致自噬相关分子靶标SESN2，LC3B和LAMP1呈激活状态，并伴随4-HNE和cleaved caspase-3损伤指标的减少，与形态学观察到的剩余毛细胞增加现象相互佐证。此外，免疫印迹分析显示，通过自噬途径上调 SESN2，促进了 反苯环丙胺作为耳保护剂的作用。反苯环丙胺干预还减少了 NOD样受体热蛋白结构域相关蛋白3的产生。总之，实验结果表明，反苯环丙胺治疗通过促进SESN2诱导自噬限制NOD样受体热蛋白结构域相关蛋白3相关炎性体信号传导来改善耳蜗炎症，这显著减轻了耳蜗毛细胞的损失并提供了听力保护，凸显了保护毛细胞免受NIHL侵害的潜在治疗策略。

https://orcid.org/0000-0002-7808-2566 (Shiming Yang); https://orcid.org/0009-0008-8265-3529 (Wei Chen); https://orcid.org/0000-0001-5970-1889 (Xi Shi); https://orcid.org/0000-0002-7153-6967 (Chang Lin)

Abstract:

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction. However, there are currently no effective pharmacological interventions for patients with noise-induced hearing loss. Here, we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss, and elucidate its underlying regulatory mechanisms. We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 dB for 4 hours. We found that tranylcypromine treatment led to the upregulation of Sestrin2 (SESN2) and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine. The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click, 4, 8, and 16 kHz frequencies compared with the noise exposure group treated with saline. These findings indicate that tranylcypromine treatment resulted in increased SESN2, light chain 3B, and lysosome-associated membrane glycoprotein 1 expression after noise exposure, leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3, thereby reducing noise-induced hair cell loss. Additionally, immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway. Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domain-containing 3 (NLRP3) production. In conclusion, our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2, which induced autophagy, thereby restricting NLRP3-related inflammasome signaling, alleviating cochlear hair cell loss, and protecting hearing function. These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Key words:

4-hydroxynonenal, apoptosis, autophagy, cleaved caspase-3,  inflammation, NOD-like receptor family pyrin domain-containing 3 (NLRP3), noise-induced hearing loss, oxidative stress, Sestrin2, tranylcypromine