Abstract
Hearing loss is often caused by death of the mechanosensory hair cells of the inner ear. Hair cells are susceptible to death caused by aging, noise trauma, and ototoxic drugs, including the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Ototoxic drugs result in permanent hearing loss for over 500 000 Americans annually. We showed previously that induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. In order to begin to translate these findings into a clinical therapy aimed at inhibiting ototoxic drug-induced hearing loss, we have now examined a pharmacological HSP inducer, celastrol. Celastrol induced upregulation of HSPs in utricles, and it provided significant protection against aminoglycoside-induced hair cell death in vitro and in vivo. Moreover, celastrol inhibited hearing loss in mice receiving systemic aminoglycoside treatment. Our data indicate that the major heat shock transcription factor HSF-1 is not required for celastrol-mediated protection. HSP32 (also called heme oxygenase-1, HO-1) is the primary mediator of the protective effect of celastrol. HSP32/HO-1 inhibits pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death. Taken together, our data indicate that celastrol inhibits aminoglycoside ototoxicity via HSP32/HO-1 induction.
Highlights
Numerous studies indicate that both reactive oxygen species (ROS) formation, and activation of c-Jun N-terminal kinase (JNK) are critical mediators of aminoglycoside-induced hair cell death.[6,7,8] Gentamicin forms a redox complex with free iron, which is capable of catalyzing the formation of ROS, including the highly reactive hydroxyl radical and lipid peroxidation products.[8]
HSP32/heme oxygenase-1 (HO-1) mRNA levels peaked 3 h post celastrol incubation (B18-fold higher than control expression). mRNA levels of both HSP27 and HSP90 were slightly elevated by celastrol
We investigated the role of HSP32/HO-1 in celastrol’s protective effect against aminoglycoside-induced hair cell death by using an HSP32/HO-1 inhibitor, zinc protoporphyrin IX (ZnPPIX)
Summary
Numerous studies indicate that both reactive oxygen species (ROS) formation, and activation of c-Jun N-terminal kinase (JNK) are critical mediators of aminoglycoside-induced hair cell death.[6,7,8] Gentamicin forms a redox complex with free iron, which is capable of catalyzing the formation of ROS, including the highly reactive hydroxyl radical and lipid peroxidation products.[8]. Total body heat stress (hyperthermia) resulted in HSP induction and significant protection against noise-induced hearing loss,[12] suggesting that HSP induction can protect sensory hair cells under stress. We showed that heat shock inhibits both aminoglycosideand cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice.[13] HSP70 is necessary for this protective effect, and constitutive expression of HSP70 is protective against aminoglycoside-induced hair cell death.[14] Importantly, HSP70 protects against hearing loss in mice exposed to systemic kanamycin.[15] Taken together, these data indicate that HSP induction is a critical stress response in the inner ear that can promote survival of hair cells exposed to major stressors.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call