Cheng Po-Wen, Liu Shing-Hwa, Young Yi-Ho, Lin-Shiau Shoei-Yn
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Toxicol Appl Pharmacol. 2006 Sep 1;215(2):228-36. doi: 10.1016/j.taap.2006.02.014. Epub 2006 Apr 19.
Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na(+), K(+)-ATPase and Ca(2+)-ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na(+), K(+)-ATPase and Ca(2+)-ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property.
顺铂已被用作化疗药物来治疗多种恶性肿瘤。其对前庭眼反射（VOR）系统的损害已有报道。然而，内耳或中枢前庭神经系统潜在的生化变化尚未完全明确。在本研究中，我们试图探究顺铂诱导的前庭毒性和D - 蛋氨酸的保护作用是否与豚鼠前庭壶腹组织以及小脑皮质（VOR系统的抑制中心）的ATP酶活性变化和氧化应激相关。通过热量试验结合眼震电图记录，我们发现顺铂暴露导致了剂量依赖性（1、3或5 mg/kg）的前庭功能障碍，表现为慢相速度（SPV）降低。此外，顺铂显著抑制了壶腹组织中的Na(+)、K(+)-ATP酶和Ca(2+)-ATP酶活性，且具有良好的剂量反应关系，但对小脑皮质的酶活性无此作用。回归分析表明，SPV的降低与壶腹组织中Na(+)、K(+)-ATP酶和Ca(2+)-ATP酶活性的降低密切相关。D - 蛋氨酸（300 mg/kg）以相关方式降低了SPV异常和ATP酶活性。此外，顺铂暴露导致前庭的脂质过氧化和一氧化氮浓度显著的剂量依赖性增加，而D - 蛋氨酸可显著抑制这种增加。然而，顺铂并未改变小脑的脂质过氧化和一氧化氮水平。总之，顺铂抑制了豚鼠前庭迷路中的ATP酶活性并增加了氧化应激。D - 蛋氨酸通过其抗氧化特性减轻了与离子紊乱相关的顺铂诱导的前庭毒性。
