Abstract
Previous studies have reported that modification of histones alters aminoglycoside-induced hair cell death and hearing loss. In this study, we investigated three FDA-approved histone deacetylase (HDAC) inhibitors (vorinostat/SAHA, belinostat, and panobinostat) as protectants against aminoglycoside-induced ototoxicity in murine cochlear explants and in vivo in both guinea pigs and CBA/J mice. Individually, all three HDAC inhibitors reduced gentamicin (GM)-induced hair cell loss in a dose-dependent fashion in explants. In vivo, however, treatment with SAHA attenuated neither GM-induced hearing loss and hair cell loss in guinea pigs nor kanamycin (KM)-induced hearing loss and hair cell loss in mice under chronic models of ototoxicity. These findings suggest that treatment with the HDAC inhibitor SAHA attenuates aminoglycoside-induced ototoxicity in an acute model, but not in chronic models, cautioning that one cannot rely solely on in vitro experiments to test the efficacy of otoprotectant compounds.
Highlights
Aminoglycoside antibiotics continue to be indispensable drugs for treatment of acute infections and for specific indications such as treatment of tuberculosis or Pseudomonas infections in patients with cystic fibrosis, owing to their broad antibacterial spectrum and efficacy against resistant bacterial strains
In order to evaluate the protective potential of the three Histone deacetylases (HDACs) inhibitors on aminoglycoside-induced ototoxicity, we first determined their safety on auditory sensory hair cells using p3 murine organ of Corti explants
An intriguing line of evidence suggests that HDAC inhibitors could prove to be an effective modality to attenuate aminoglycoside-induced ototoxicity in acute models
Summary
Aminoglycoside antibiotics continue to be indispensable drugs for treatment of acute infections and for specific indications such as treatment of tuberculosis or Pseudomonas infections in patients with cystic fibrosis, owing to their broad antibacterial spectrum and efficacy against resistant bacterial strains. Their use has been limited due to ototoxic and nephrotoxic side effects. A pathological feature of aminoglycoside-induced ototoxicity is loss of mechanosensory hair cells in the inner ear, resulting in hearing loss and vestibular dysfunction. There have been efforts to find potential therapies to mitigate these side effects, no established clinical therapies for prevention or amelioration are yet available
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