Selective GSK-3β inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells
Selective GSK-3β inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells
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DOI：
10.1016/j.heares.2009.08.001
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发表时间：
2009-11-01
期刊：
影响因子：
2.8
通讯作者：
Park, Sung-Joo
中科院分区：
文献类型：
--
作者：
Park, Hee-Je;Kim, Hyung-Jin;Park, Sung-Joo
糖原合成酶激酶3 （GSK-3）在细胞凋亡的调控中起重要作用。然而，GSK-3在听觉系统中的作用尚不清楚。在这里，我们研究了gsk -3特异性抑制剂SB 216763和LiCl是否可以保护听觉细胞免受顺铂诱导的细胞毒性。顺铂处理hell - oc1细胞后GSK-3被激活。SB 216763或LiCl以剂量依赖的方式抑制顺铂诱导的细胞凋亡，并激活caspase-9、-8和-3。在大鼠Corti器官原代外植体中，SB 216763或LiCl处理完全消除了顺铂诱导的外毛细胞阵列的破坏。给药SB 216763或LiCl可抑制顺铂注射小鼠耳蜗破坏及肿瘤坏死因子- α (tnf - α)、白细胞介素-1 β (IL-1 β)和IL-6的产生。此外，给药SB 216763或LiCl降低了顺铂注射小鼠听觉脑干反应（ABR）的阈值。综上所述，这些结果表明顺铂诱导的耳毒性可能与GSK-3激活的调节有关。(C) 2009 Elsevier B.V.版权所有
Glycogen synthase kinase-3 (GSK-3) plays an important role in the regulation of apoptosis. However, the role of GSK-3 in the auditory system remains unknown. Here we examined whether the GSK-3-specific inhibitors, SB 216763 and LiCl, could protect against cisplatin-induced cytotoxicity of auditory cells. GSK-3 was activated by cisplatin treatment of HEl-OC1 cells. SB 216763 or LiCl treatments inhibited cisplatin-induced apoptosis in a dose-dependent manner and activated caspase-9, -8 and -3. In rat primary explants of the organ of Corti, SB 216763 or LiCl treatments completely abrogated the cisplatin-induced destruction of outer hair cell arrays. Administration of SB 216763 or LiCl inhibited cochlear destruction and the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-6 in cisplatin-injected mice. Furthermore, administration of SB 216763 or LiCl reduced the thresholds of the auditory brainstem response (ABR) in cisplatin-injected mice. Collectively, these results suggest that cisplatin-induced otortoxicity might be associated with modulation of GSK-3 activation. (C) 2009 Elsevier B.V. All rights reserved.