Selective GSK-3β inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells

• Published in: Hearing research 2009-11, Vol.257 (1), p.53-62
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cochlea; Drug toxicity and drugs side effects treatment; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; GSK-3; Hair cell; Hearing loss; Medical sciences; Non tumoral diseases; Otorhinolaryngology. Stomatology; Ototoxicity; Pharmacology. Drug treatments; Toxicity: respiratory system, ent, stomatology
• ISSN: 0378-5955; 1878-5891
• DOI: 10.1016/j.heares.2009.08.001

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-α (TNF-α), interleukin-1β (IL-1β) 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.