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.

Sound preconditioning therapy inhibits ototoxic hearing loss in mice

“…Heat shock protein (HSP) induction is a critical stress response in the inner ear that can promote survival of hair cells exposed to both classes of ototoxic drugs (1)(2)(3)(4)(5). Given that HSP induction is a ubiquitous response to stress (6), we hypothesized that sound that is loud enough to stress the inner ear without causing permanent damage would induce HSPs and inhibit ototoxic drug-induced hearing loss.…”

Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells

“…Notably, the anti-ototoxicity property of Celastrol has been revealed recently through induction of heat shock protein 32 to suppress both aminoglycoside- and cisplatin-induced hair cell death. 20 Moreover, Celastrol administration significantly rescued the hearing loss in mice receiving systematic aminoglycoside treatment. Mechanistically, Celastrol induced HSP32 expression, which in turn inhibited pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death.…”

“…Mechanistically, Celastrol induced HSP32 expression, which in turn inhibited pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death. 20 In view of the protective effect of Celastrol on aminoglycoside antibiotics and anti-neoplastic agent caused hair cell death, 20 here we sought to investigate the potential benefit of Celastrol on inner ear stem cells, which is believed to be permanently dormant in adult mammalian auditory system. In line with the protective effect against ototoxicity, here we demonstrated that 2 μM Celastrol treatment remarkably improved the viability and proliferation of isolated inner ear stem cells in vitro.…”

“…18 In addition, Celastrol treatment triggered heat shock response via inducing HSP70 expression. 19 Most importantly, Celastrol has been demonstrated to inhibit aminoglycoside-induced ototoxicity via heat shock protein 32 induction, 20 which prompted us to further hypothesize that Celastrol could confer beneficial effect on inner ear stem cells, and have the potential as adjuvant treatment for stem cell therapy against hearing loss.…”

Genes and Hearing Loss: Relationship to Oxidative Stress and Free Radical Formation

“…The triterpene compound celastrol has been shown to protect vestibular and cochlear hair cells from aminoglycoside toxicity (Francis et al 2011 ). Celastrol's protective activity appears to be through induction of Hsp32 expression, which occurs even in an Hsf1 null mutant background, and is associated with inhibition of JNK-mediated apoptosis.…”