Histone Deacetylase Inhibitors Are Protective in Acute but Not in Chronic Models of Ototoxicity

Area of Science:

• Ototoxicity research
• Pharmacology
• Neuroscience

Background:

• Aminoglycoside antibiotics can cause ototoxicity, leading to hearing loss and hair cell death.
• Histone modification plays a role in aminoglycoside-induced ototoxicity.
• Histone deacetylase (HDAC) inhibitors are being explored for therapeutic potential.

Purpose of the Study:

• To investigate the otoprotective effects of three FDA-approved HDAC inhibitors against aminoglycoside-induced ototoxicity.
• To evaluate the efficacy of vorinostat (SAHA), belinostat, and panobinostat in both in vitro and in vivo models.
• To determine if HDAC inhibitors are effective in acute versus chronic ototoxicity models.

Main Methods:

• Utilized murine cochlear explants for in vitro studies.
• Conducted in vivo studies in guinea pigs and CBA/J mice.
• Administered gentamicin (GM) and kanamycin (KM) to induce ototoxicity.
• Assessed hair cell loss and hearing loss following HDAC inhibitor treatment.

Main Results:

• All three HDAC inhibitors demonstrated dose-dependent reduction of gentamicin-induced hair cell loss in cochlear explants.
• Vorinostat (SAHA) did not attenuate gentamicin-induced ototoxicity in guinea pigs under chronic conditions.
• SAHA also failed to protect against kanamycin-induced hearing and hair cell loss in mice in chronic models.

Conclusions:

• HDAC inhibitors, specifically SAHA, show efficacy in acute aminoglycoside-induced ototoxicity models.
• SAHA's protective effects were not observed in chronic ototoxicity models.
• In vitro results may not fully predict in vivo efficacy in chronic ototoxicity, cautioning against sole reliance on such models for otoprotectant development.