MnTBAP在顺铂诱导的听力损失中的耳保护作用。

文献信息

中文摘要

目的： 顺铂是一种挽救生命的化疗药物，可引起耳毒性。尽管硫代硫酸钠用于预防儿科患者的耳毒性，但尚无其他干预措施被批准用于临床对抗顺铂诱导的听力损失。因此，迫切需要识别预防顺铂耳毒性的药物。
方法： CBA/J小鼠接受顺铂治疗（3 mg/kg，腹腔注射，每日一次，连续5天），并使用MnTBAP（10 mg/kg，腹腔注射，每日一次，连续8天）抑制顺铂诱导的耳毒性。在治疗前后记录听性脑干反应（ABRs）和畸变产物耳声发射（DPOAEs）以评估听力损失，同时进行免疫组织化学染色：抗Myosin-VIIa用于检查毛细胞丢失，鬼笔环肽用于检查螺旋神经节神经元（SGN）丢失，抗硝基酪氨酸用于评估硝基酪氨酸水平。
结果： 顺铂治疗提高了毛细胞和SGN中的硝基酪氨酸水平，并增加了耳蜗中部和基底区的这些细胞丢失。观察到顺铂诱导的毛细胞计数或SGN密度变化与硝基酪氨酸水平之间呈负相关。顺铂治疗提高了ABRs所示的听阈，并降低了DPOAE振幅，表明顺铂诱导的听力损失。然而，MnTBAP联合治疗阻止了顺铂诱导的听力敏感性变化，并逆转了形态学变化。
结论： MnTBAP联合治疗观察到的耳保护作用以及顺铂诱导的耳蜗硝基酪氨酸水平升高的减弱，表明其作为耳蜗硝化应激抑制剂的潜力及其在减轻顺铂诱导的耳毒性中的效用。

英文摘要

OBJECTIVE: Cisplatin, a life-saving chemotherapeutic drug, causes ototoxicity. Although sodium thiosulfate is used to prevent ototoxicity in pediatric patients, no other intervention has been approved for clinical use against cisplatin-induced hearing loss. Hence, there is an urgent need to identify drugs that prevent cisplatin ototoxicity.
METHODS: CBA/J mice were treated with cisplatin (3 mg/kg, i.p., daily for 5 days), and MnTBAP (10 mg/kg, i.p., daily for 8 days) was used to inhibit cisplatin-induced ototoxicity. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were recorded before and after treatment to assess hearing loss, while immunohistochemistry with anti-Myosin-VIIa was conducted to examine hair cell loss, with phalloidin to examine spiral ganglion neuron (SGN) loss, and with anti-nitrotyrosine to assess nitrotyrosine levels.
RESULTS: Cisplatin treatment elevated the nitrotyrosine levels in hair cells and SGNs and increased the loss of these cells in the middle and basal cochlear regions. A negative correlation was observed between cisplatin-induced changes in the hair cell count or SGN density and nitrotyrosine levels. Cisplatin treatment elevated the hearing thresholds, as indicated by the ABRs, and lowered the DPOAE amplitudes, suggesting cisplatin-induced hearing loss. However, MnTBAP cotreatment prevented the cisplatin-induced changes in hearing sensitivity and reversed the morphological changes.
CONCLUSION: The otoprotection observed with MnTBAP cotreatment along with the attenuation of cisplatin-induced increase in nitrotyrosine levels in the cochlea indicates its potential as an inhibitor of cochlear nitrative stress and its utility in mitigating cisplatin-induced ototoxicity.