Park Hee-Je, Kim Hyung-Jin, Bae Gi-Sang, Seo Sang-Wan, Kim Do-Yun, Jung Won-Seok, Kim Min-Sun, Song Mi-Young, Kim Eun-Kyung, Kwon Kang-Beom, Hwang Sung-Yeon, Song Ho-Joon, Park Cheung-Seog, Park Rae-Kil, Chong Myong-Soo, Park Sung-Joo
Department of Herbology, College of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, South Korea.
Hear Res. 2009 Nov;257(1-2):53-62. doi: 10.1016/j.heares.2009.08.001. Epub 2009 Aug 8.
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 HEI-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-1beta (IL-1beta) 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 ototoxicity might be associated with modulation of GSK-3 activation.
糖原合酶激酶-3（GSK-3）在细胞凋亡调控中发挥重要作用。然而，GSK-3在听觉系统中的作用尚不清楚。在此，我们研究了GSK-3特异性抑制剂SB 216763和LiCl是否能预防顺铂诱导的听觉细胞毒性。顺铂处理HEI-OC1细胞可激活GSK-3。SB 216763或LiCl处理以剂量依赖方式抑制顺铂诱导的细胞凋亡，并激活半胱天冬酶-9、-8和-3。在大鼠柯蒂氏器原代外植体中，SB 216763或LiCl处理完全消除了顺铂诱导的外毛细胞阵列破坏。给予SB 216763或LiCl可抑制顺铂注射小鼠的耳蜗破坏以及肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和IL-6的产生。此外，给予SB 216763或LiCl可降低顺铂注射小鼠的听觉脑干反应（ABR）阈值。总体而言，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。
