Selective GSK-3beta inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells.
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.
Park
Hee-Je
HJ
Department of Herbology, College of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, South Korea. tajohj82@hanmail.net
Kim
Hyung-Jin
HJ
Bae
Gi-Sang
GS
Seo
Sang-Wan
SW
Kim
Do-Yun
DY
Jung
Won-Seok
WS
Kim
Min-Sun
MS
Song
Mi-Young
MY
Kim
Eun-Kyung
EK
Kwon
Kang-Beom
KB
Hwang
Sung-Yeon
SY
Song
Ho-Joon
HJ
Park
Cheung-Seog
CS
Park
Rae-Kil
RK
Chong
Myong-Soo
MS
Park
Sung-Joo
SJ
D000161:Acoustic Stimulation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000201:enzymology; D034381:Hearing Loss / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D018021:Lithium Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D008301:Maleimides / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D009925:Organ of Corti / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000970:Antineoplastic Agents; D007211:Indoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C417521:SB 216763; D014409:Tumor Necrosis Factor-alpha; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D020169:Caspases; D018021:Lithium Chloride; D002945:Cisplatin