Aminoglycoside‐induced histone deacetylation and hair cell death in the mouse cochlea

Abstract

Post-translational modification of histones is an important form of chromatin regulation impacting transcriptional activation. Histone acetyltransferases (HATs), for example, acetylate lysine residues on histone tails enhancing gene transcription, while histone deacetylases (HDACs) remove those acetyl groups and repress gene transcription. Deficient histone acetylation is associated with pathologies, and histone deacetylase inhibitors have been studied in the treatment of cancer and neurodegenerative diseases. Here we explore histone acetylation in cochlear sensory cells following a challenge with gentamicin, an aminoglycoside antibiotic known to cause loss of auditory hair cells and hearing. The addition of the drug to organotypic cultures of the mouse organ of Corti decreased the acetylation of histone core proteins (H2A Ack5, H2B Ack12, H3 Ack9, and H4 Ack8) followed by a loss of sensory cells. Protein levels of HDAC1, HDAC3 and HDAC4 were increased while the HATs CBP and p300 remained unchanged. We next hypothesized that protecting histone acetylation should prevent cell death and tested the effects of HDAC-inhibitors on the actions of gentamicin. Co-treatment with trichostatin-A maintained near-normal levels of acetylation of histone core proteins in cochlear outer hair cells and attenuated gentamicin-induced cell death. The addition of sodium butyrate also rescued hair cells from damage by gentamicin. The results are consistent with an involvement of deficient histone acetylation in aminoglycoside-induced hair cell death by and point to the potential value of HDAC-inhibitors in protection from the side effects of these drugs.

Macrophage migration inhibitory factor acts as a neurotrophin in the developing inner ear

“…Inner ears were isolated from mice at postnatal day (P) 3 (Chen et al, 2009); organs of Corti (OC) and spiral ganglia (SG) were isolated from age-matched wild-type mice (Balb/c, WT) and Mif KO mice. The OC explants (WT or Mif KO) were then placed 1 cm from the SG explants (n=12 per condition).…”

The Effects of Hyperbaric Oxygen Therapy Against Streptomycin Ototoxicity

“…According to the accumulated informations obtained from previous reports, the most reasonable cause for the increase in apoptosis could be the excess free-radical agent accumulation. If free-radical agents are present at high concentrations, they are thought to act as a cytotoxin and can kill cells [4,5]. Then those dead cells (e.g., sensory hair cells) can be demonstrated histopathologically with caspase-3 as in the present study.…”

“…Aminoglycoside antibiotics may injure the outer hair cells at the basal turn of the cochlea and cause sensorineural hearing loss. In more severe cases, the damage may progress to inner hair cells and supporting cells [4][5][6]. Therefore, it is important to identify the development mechanism and subsequently prevention methods against to vestibulotoxicity and cochleotoxicity.…”

“…After almost eight decades in clinical use, although the ototoxic effects of aminoglycosides in animals and humans are well documented and also high occurrence risk of another serious complication such as nephrotoxicity, this class of drugs seems still likely to remain an important component of medical treatment options due to: 1) the effectiveness at the treatment of gramnegative aerobic bacterial infections, 2) being an alternative medication among the rare options of treatment in tuberculosis, 3) beneficial effects in Meniere's disease and 4) relatively low cost [1][2][3][4][5][6]. Aminoglycoside antibiotics may injure the outer hair cells at the basal turn of the cochlea and cause sensorineural hearing loss.…”

“…For this aim, a great effort has been made and several studies have been conducted to develop strategies and to find a way out against to aminoglycoside-induced ototoxicity. Among them, anti-free radical agents are becoming increasingly important [4][5]. Hyperbaric oxygen (HBO) therapy, having an important antioxidant activity, is based on inhalation of 100% oxygen under pressures above 1 atm (pressurized between 1.5 and 3.0 atmosphere absolute) in a pressure chamber [7,8].…”