Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acoustic Stimulation
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / toxicity*
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Apoptosis / drug effects
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Caspases / metabolism
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Cell Line
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Cisplatin / administration & dosage
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Cisplatin / toxicity*
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Activation
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Evoked Potentials, Auditory, Brain Stem / drug effects
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Hair Cells, Auditory / drug effects
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Hair Cells, Auditory / enzymology
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Hearing Loss / chemically induced
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Hearing Loss / enzymology
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Hearing Loss / pathology
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Hearing Loss / physiopathology
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Hearing Loss / prevention & control*
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Indoles / administration & dosage
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Indoles / pharmacology*
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Injections, Intraperitoneal
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Interleukin-1beta / blood
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Interleukin-6 / blood
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Lithium Chloride / administration & dosage
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Lithium Chloride / pharmacology*
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Maleimides / administration & dosage
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Maleimides / pharmacology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Organ Culture Techniques
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Organ of Corti / drug effects*
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Organ of Corti / enzymology
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Organ of Corti / pathology
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Organ of Corti / physiopathology
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Time Factors
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Tumor Necrosis Factor-alpha / blood
Substances
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Antineoplastic Agents
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Indoles
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Interleukin-1beta
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Interleukin-6
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Maleimides
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Protein Kinase Inhibitors
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SB 216763
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Tumor Necrosis Factor-alpha
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Gsk3b protein, rat
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Glycogen Synthase Kinase 3
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Caspases
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Lithium Chloride
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Cisplatin