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Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32

S P Francis1, I I Kramarenko, C S Brandon

  • 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.

Cell Death & Disease
|August 26, 2011
PubMed

Insights

Celastrol protects against hearing loss caused by ototoxic drugs by inducing heat shock proteins (HSPs). This compound, specifically HSP32/HO-1, prevents hair cell death and inhibits hearing impairment.

Area of Science:

  • Ototoxicity and Hearing Loss Research
  • Molecular Mechanisms of Cell Death
  • Pharmacological Interventions for Hearing Protection

Background:

  • Mechanosensory hair cells in the inner ear are vulnerable to damage from aging, noise, and ototoxic drugs like aminoglycosides and cisplatin.
  • Ototoxic drug-induced hearing loss affects over 500,000 Americans annually, leading to permanent hearing impairment.
  • Previous research demonstrated that heat shock proteins (HSPs) can inhibit aminoglycoside- and cisplatin-induced hair cell death.

Purpose of the Study:

  • To investigate celastrol, a pharmacological heat shock protein (HSP) inducer, as a potential therapeutic agent to prevent ototoxic drug-induced hearing loss.
  • To determine the mechanism by which celastrol confers protection against aminoglycoside ototoxicity.
  • To assess the role of heat shock factor 1 (HSF-1) and HSP32/heme oxygenase-1 (HO-1) in celastrol-mediated protection.

Main Methods:

  • Administered celastrol to mouse utricle cultures and live mice to assess its effect on HSP induction and hair cell survival.
  • Evaluated the protective effects of celastrol against aminoglycoside-induced hair cell death in vitro and in vivo.
  • Investigated the involvement of HSF-1 and HSP32/HO-1 in the protective mechanism using genetic and molecular approaches.

Main Results:

  • Celastrol successfully induced HSPs in mouse utricles and provided significant protection against aminoglycoside-induced hair cell death.
  • Celastrol treatment inhibited hearing loss in mice subjected to systemic aminoglycoside administration.
  • The protective effect of celastrol was independent of HSF-1 and primarily mediated by HSP32/HO-1 induction, which suppressed c-Jun N-terminal kinase (JNK) activation.

Conclusions:

  • Celastrol is a potent inducer of HSPs and offers significant protection against aminoglycoside-induced ototoxicity.
  • HSP32/HO-1 is the key mediator of celastrol's protective effects, acting by inhibiting JNK signaling and subsequent hair cell death.
  • Celastrol represents a promising therapeutic strategy for preventing hearing loss caused by ototoxic drugs.

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