lithium-chloride and Hearing-Loss

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.

Topics: Acoustic Stimulation; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Line; Cisplatin; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Evoked Potentials, Auditory, Brain Stem; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hair Cells, Auditory; Hearing Loss; Indoles; Injections, Intraperitoneal; Interleukin-1beta; Interleukin-6; Lithium Chloride; Maleimides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organ Culture Techniques; Organ of Corti; Phosphorylation; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Time Factors; Tumor Necrosis Factor-alpha