ENDOGENOUS MODULATION OF COCHLEAR INJURY

耳蜗损伤的内源性调节

• 批准号: 6174958
• 负责人: LEONARD P RYBAK
• 金额: $ 23.78万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174958
• 关键词: antioxidants; atomic absorption spectrometry; audiometry; auditory nuclei; catalase; chemoprevention; cis platinum compound; cochlea; cochlear microphonic potentials; drug interactions; ear pharmacology; electron microscopy; enzyme activity; glutathione; glutathione peroxidase; glutathione reductase; glutathione transferase; laboratory rat; lipid peroxides; malonaldehyde; organ of Corti; ototoxin; pharmacokinetics; superoxide dismutase; thiocarbamate

The optimal use of cisplatin for the best treatment of solid tumors has been prevented because of dose limiting nephro-and ototoxicity. Higher doses of cisplatin may be used with chemoprotectants such as diethyldithiocarbamate (DDTC), which prevents cisplatin toxicity for the kidney and bone marrow. Our preliminary data suggest that DDTC can also prevent cisplatin ototoxicity in an animal model. The proposed research seeks to address the basic question, "Can the ototoxicity of cisplatin be altered by manipulating the glutathione (GSH) content of the cochlea?" A corollary is that the GSH content of the cochlea is related to enzymes of the antioxidant system [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)] and the enzymes glutathione reductase (GR) and glutathione-S-transferase (GST) and that these enzymes are affected by cisplatin. The specific aims are: 1) to investigate the hypothesis that cisplatin ototoxicity is related to the diminution of the antioxidant system in the cochlea, and that such changes are specific for this target tissue. Physiological changes measured with auditory brainstem evoked response (ABER) testing and endocochlear potential (EP) measurements will be correlated with a) ultrastructural alterations using scanning electron microscopy (SEM) of the organ of Corti and transmission electron microscopy (TEM) of the stria vascularis; and b) biochemical changes in the antioxidant system of the cochlea in comparison to nontarget tissues, the liver and heart, 2) to test the hypothesis that some or all of the ototoxic injury caused by cisplatin is mediated by ototoxic metabolites such as GSH adducts, 3) to examine the hypothesis that the prevention of cisplatin ototoxicity by DDTC is mediated by preservatives of the antioxidant system in the cochlea, 4) to study the pharmacokinetics of cisplatin in plasma and cochlear tissues in ototoxic rats and in animals receiving cisplatin plus the rescue agent, DDTC. The techniques used for this investigation will involve the expertise of three investigators namely physiological measurements (ABER and EP), morphological studies (SEM and TEM) biochemical and metabolic studies: (HPLC) with ultraviolet and electrochemical detection (GSH and GSSG), antioxidant enzymes and other enzymes of the glutathione pathway using spectrophotometry and pharmacokinetic studies by atomic absorption spectrophotometry of platinum levels. These studies should provide new insights into the mechanisms of cisplatin ototoxicity and mechanisms for protection from this dose-limiting side effect arising from use of this life-saving chemotherapeutic agent.

顺铂的最佳用途用于实体瘤的最佳治疗 由于剂量限制肾毒性而被阻止。更高 剂量的顺铂可以与化学保护剂（例如 Diethyldithiocaramate（DDTC），可防止顺铂毒性 肾脏和骨髓。我们的初步数据表明DDTC也可以 防止动物模型中的顺铂耳毒性。拟议的研究 试图解决一个基本问题：“顺铂的耳毒性可以是 通过操纵耳蜗的谷胱甘肽（GSH）含量而改变？ 推论是耳蜗的GSH含量与 抗氧化剂系统[超氧化物歧化酶（SOD），过氧化氢酶（CAT）和 谷胱甘肽过氧化物酶（GSH-PX）和谷胱甘肽还原酶 （GR）和谷胱甘肽-S-转移酶（GST），这些酶是 受顺铂影响。具体目的是：1）调查 假设顺铂耳毒性与减少 耳蜗中的抗氧化剂系统，这种变化是特定的 该靶组织。用听觉脑干测量的生理变化 诱发的反应（ABER）测试和内凝度势（EP） 测量将与a）使用的超微结构改变相关 Corti和传播器官的扫描电子显微镜（SEM） 血管丝肌的电子显微镜（TEM）； b）生化 与之相比 非核组织，肝脏和心脏，2）检验以下假设。 由顺铂引起的一些或全部耳毒性损伤是由 耳毒性代谢物，例如GSH加合物，3）检查假设 DDTC介导的DDTC预防顺铂耳毒性 耳蜗中抗氧化系统的防腐剂，4） 在耳毒性中血浆和耳蜗组织中顺铂的药代动力学 大鼠和接受顺铂的动物加上救援剂DDTC。这 用于此调查的技术将涉及三个专业知识 研究人员是生理测量（Aber和EP）， 形态学研究（SEM和TEM）生化和代谢研究： （HPLC）紫外线和电化学检测（GSH和GSSG）， 使用谷胱甘肽途径的抗氧化酶和其他酶 分光光度法和药代动力学研究通过原子吸收 铂水平的分光光度法。这些研究应该提供新的 洞悉顺铂耳毒性的机制和机制 防止使用此剂量限制副作用 挽救生命的化学治疗剂。