Whitworth Craig A, Ramkumar Vickram, Jones Brett, Tsukasaki Naoki, Rybak Leonard P
Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL 62794-9230, USA.
Biochem Pharmacol. 2004 May 1;67(9):1801-7. doi: 10.1016/j.bcp.2004.01.010.
Cisplatin is a commonly used antineoplastic agent that causes ototoxicity through the formation of reactive oxygen species (ROS). Previous studies have shown that cisplatin causes an upregulation of A(1) adenosine receptor (A(1)AR) in the cochlea, and that application of the adenosine agonist, R-phenylisopropyladenosine (R-PIA), to the round window (RW) results in significant increases in cochlear glutathione peroxidase and superoxide dismutase. These data suggest that adenosine receptors (ARs) are an important part of the cytoprotective system of the cochlea in response to oxidative stress. The purpose of the current study was to investigate the effect of various adenosine agonists on cisplatin ototoxicity using RW application. Auditory brainstem response (ABR) thresholds were recorded in anesthetized chinchillas at 1, 2, 4, 8 and 16kHz. The auditory bullae were surgically opened, and 1mM R-PIA, 10microM 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)/R-PIA (1mM) cocktail, 100microM 2-chloro-N-cyclopentyladenosine (CCPA), 2-[4-(2-p-carboxy-ethyl)phenylamino]-5'-N-ethylcarboxamidoadenosine (CGS) or vehicle were applied to the RW. After 90min, the remaining solution was removed and cisplatin was applied to the RW. The bullae were closed and the animals recovered for 72h, after which, follow-up ABRs were performed. Cochleae were harvested for scanning electron microscopy (SEM) and for lipid peroxides. Pre-administration of the A(1)AR agonists R-PIA or CCPA significantly reduced cisplatin-induced threshold changes at all but the highest test frequency. In addition, A(1)AR agonists protected against cisplatin-induced hair cell damage and significantly reduced cisplatin-induced lipid peroxidation. Co-administration of the A(1)AR antagonist, DPCPX, completely reversed the protective effects of R-PIA. In contrast, pretreatment with CGS-21680, an A(2A) adenosine receptor (A(2A)AR) agonist, significantly increased cisplatin-induced threshold changes. Our findings are consistent with the notion that the A(1)AR contributes significantly to cytoprotection in the cochlea, and thereby protects against hearing loss.
顺铂是一种常用的抗肿瘤药物，它通过产生活性氧（ROS）导致耳毒性。先前的研究表明，顺铂会使耳蜗中的A(1)腺苷受体（A(1)AR）上调，并且将腺苷激动剂R-苯异丙基腺苷（R-PIA）应用于圆窗（RW）会导致耳蜗谷胱甘肽过氧化物酶和超氧化物歧化酶显著增加。这些数据表明，腺苷受体（ARs）是耳蜗细胞保护系统应对氧化应激的重要组成部分。本研究的目的是通过圆窗给药研究各种腺苷激动剂对顺铂耳毒性的影响。在麻醉的毛丝鼠中记录1、2、4、8和16kHz的听觉脑干反应（ABR）阈值。手术打开听泡，将1mM R-PIA、10μM 8-环戊基-1,3-二丙基黄嘌呤（DPCPX）/R-PIA（1mM）混合物、100μM 2-氯-N-环戊基腺苷（CCPA）、2-[4-(2-对羧基乙基)phenylamino]-5'-N-乙基羧酰胺腺苷（CGS）或赋形剂应用于圆窗。90分钟后，去除剩余溶液并将顺铂应用于圆窗。关闭听泡，动物恢复72小时，之后进行后续ABR测试。收获耳蜗用于扫描电子显微镜（SEM）检查和脂质过氧化物检测。在除最高测试频率外的所有频率下，预先给予A(1)AR激动剂R-PIA或CCPA可显著降低顺铂诱导的阈值变化。此外，A(1)AR激动剂可防止顺铂诱导的毛细胞损伤，并显著降低顺铂诱导的脂质过氧化。联合给予A(1)AR拮抗剂DPCPX可完全逆转R-PIA的保护作用。相反，用A(2A)腺苷受体（A(2A)AR）激动剂CGS-21680预处理可显著增加顺铂诱导的阈值变化。我们的研究结果与以下观点一致，即A(1)AR对耳蜗的细胞保护作用有显著贡献，从而防止听力损失。
