Estradiol protects the cochlea against gentamicin ototoxicity through inhibition of the JNK pathway.
Gentamicin induces outer hair cell death through the apoptotic pathway. It has been reported that this death pathway of outer hair cells is mediated by specific apoptotic enzymes including c-jun N-terminal kinase (JNK) and caspases. 17beta-Estradiol (E2), the most potent estrogen, is known to function as an antiapoptotic agent to prevent the death of various cell types. The purpose of the present study was to examine the effects of E2 on gentamicin-induced apoptotic cell death in outer hair cells. The basal turn organ of Corti explants from p3 or p4 rats were maintained in a tissue culture and exposed to 100muM gentamicin for 48h. The effects of E2 on gentamicin-induced outer hair cell loss, JNK activation, and staining for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling (TUNEL) were examined. E2 significantly decreased gentamicin-induced outer hair cell loss in a dose-dependent manner. JNK activation and TUNEL staining were observed in organ of Corti explants exposed to gentamicin, and staining levels were significantly decreased by E2 treatment. The results indicate that, through the inhibition of JNK and subsequent apoptotic reactions, E2 decreases outer hair cell loss induced by gentamicin ototoxicity.
Nakamagoe
Mariko
M
Department of Otolaryngology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
Tabuchi
Keiji
K
Uemaetomari
Isao
I
Nishimura
Bungo
B
Hara
Akira
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D005839:Gentamicins / Q000494:pharmacology* / Q000633:toxicity; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D004958:Estradiol; D048670:MAP Kinase Kinase 4; D020169:Caspases