title: Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Francis
authors.forename: I I
authors.initials: II
authors.lastname: Kramarenko
authors.forename: C S
authors.initials: CS
authors.lastname: Brandon
authors.forename: F-S
authors.initials: FS
authors.lastname: Lee
authors.forename: T G
authors.initials: TG
authors.lastname: Baker
authors.forename: L L
authors.initials: LL
authors.lastname: Cunningham
mesh_terms: D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis; D002945:Cisplatin / Q000633:toxicity; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034381:Hearing Loss / Q000139:chemically induced; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D023421:Models, Animal; D053978:Pentacyclic Triterpenes; D012444:Saccule and Utricle / Q000187:drug effects / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D051547:Heme Oxygenase-1; D048031:JNK Mitogen-Activated Protein Kinases; C050414:celastrol; D002945:Cisplatin