A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

Aminoglycosides (AG) such as amikacin are commonly used in cystic fibrosis patients with opportunistic pulmonary infections including multi-drug resistant mycobacterium tuberculous and non-tuberculous mycobacterium. Unfortunately, this class of drugs is known to cause peripheral damage to the cochlea leading to hearing loss that can fluctuate and become permanent over time or multiple exposures. However, whether amikacin can lead to central auditory dysfunction like hyperacusis (increased sensitivity to sound) or tinnitus (perception of sound in the absence of acoustic stimulation) is not well-described in the literature. Thus, an animal model needs to be developed that documents these side effects in order to develop therapeutic solutions to reduce AG-induced auditory dysfunction. Here we present pioneer work in mice which demonstrates that amikacin can lead to fluctuating behavioral evidence of hyperacusis and tinnitus as assessed by the acoustic startle reflex. Additionally, electrophysiological assessments of hearing via auditory brainstem response demonstrate increased central activity in the auditory brainstem. These data together suggest that peripheral AG-induced dysfunction can lead to central hyperactivity and possible behavioral manifestations of hyperacusis and tinnitus. Importantly, we demonstrate that ebselen, a novel investigational drug that acts as both an antioxidant and anti-inflammatory, can mitigate AG-induced hyperacusis.