Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.
Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.
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DOI：
10.1093/toxsci/47.2.195
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发表时间：
1999-02
期刊：
影响因子：
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通讯作者：
Leonard P. Rybak;K. Husain;C. Whitworth;Satu M. Somani
中科院分区：
文献类型：
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作者：
Leonard P. Rybak;K. Husain;C. Whitworth;Satu M. Somani
本研究调查了顺铂诱导的耳毒性和抗氧化脂酸盐剂量依赖性耳保护中耳蜗谷胱甘肽（GSH）浓度、脂质过氧化和抗氧化酶活性变化同时发生的听性脑干诱发反应（ABRs）的改变。雄性Wistar大鼠分为不同组，处理方法如下：(1)对照（生理盐水）；(2)顺铂（16 mg/kg， 1次）；(3)脂酸盐（100mg /kg， 1次）加生理盐水；(4)顺铂加硫酸盐（25 mg/kg）；(5)顺铂加硫酸盐（50 mg/kg）和(6)顺铂加硫酸盐（100 mg/kg）。治疗后3天后评估abr，处死大鼠，摘取耳蜗进行分析。注射顺铂大鼠ABR阈值高于治疗前阈值。用脂酸盐加顺铂治疗的大鼠听力阈值没有明显升高。顺铂治疗导致耳蜗GSH浓度降低（占对照组的69%），而顺铂加硫酸盐治疗使GSH浓度升高，接近对照组。顺铂治疗大鼠耳蜗超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-Px）和谷胱甘肽还原酶（GR）活性降低（分别为对照组的57%、78%、59%和58%），丙二醛（MDA）浓度升高（对照组的196%）。与单用顺铂组相比，顺铂加分级剂量脂酸组大鼠耳蜗SOD、CAT、GSH-Px、GR活性和MDA浓度均有所恢复。由此可见，顺铂诱导的耳毒性与耳蜗抗氧化防御系统的损伤有关，抗氧化脂酸盐对顺铂耳毒性的剂量依赖性耳保护与耳蜗抗氧化防御系统的保护有关。
This study investigated the alterations that occur in auditory brainstem-evoked responses (ABRs) concurrent with changes in cochlear concentrations of glutathione (GSH), lipid peroxidation, and antioxidant enzyme activity in cisplatin-induced ototoxicity and in dose-dependent otoprotection by an antioxidant lipoate. Male Wistar rats were divided into different groups and were treated as follows, with: (1) vehicle (saline) control; (2) cisplatin (16 mg/kg, i.p.); (3) lipoate (100 mg/kg, i.p.) plus saline; (4) cisplatin plus lipoate (25 mg/kg); (5) cisplatin plus lipoate (50 mg/kg), and (6) cisplatin plus lipoate (100 mg/kg). Post-treatment ABRs were evaluated after three days, the rats were sacrificed, and cochleae were harvested and analyzed. The cisplatin-injected rats showed ABR threshold elevations above the pre-treatment thresholds. Rats treated with lipoate plus cisplatin did not show significant elevation of hearing thresholds. Cisplatin administration resulted in a depletion of cochlear GSH concentration (69% of control), whereas, cisplatin-plus-lipoate treatment increased GSH concentration close to control value. Cisplatin-treated rats showed a decrease in cochlear superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities (57, 78, 59, and 58% of control, respectively), and an increase in malondialdehyde (MDA) concentration (196% of control). Cochlear SOD, CAT, GSH-Px, and GR activities and MDA concentrations were restored in the rats injected with cisplatin plus graded doses of lipoate than those with cisplatin alone. It is concluded that cisplatin-induced ototoxicity is related to impairment of the cochlear antioxidant defense system, and the dose-dependent otoprotection conferred by an antioxidant lipoate against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant defense system.