Abstract
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.
Highlights
Aminoglycoside (AG) antibiotics are the most prevalent treatment option for cystic fibrosis (CF) and other lifethreatening gram-negative bacterial infections (Flume et al, 2009; Drusano and Louie, 2011)
Following a standard 14-day amikacin regimen (2 weeks), auditory brainstem response (ABR) thresholds were only slightly elevated (∼5 dB) from baseline levels and no significant differences were observed between groups [F(2,193) = 3.039, p = 0.0502] (Figure 2A)
These findings taken together show that amikacin given at this dose in mice caused a mild fluctuating hearing loss which recovered by 14 weeks after the start of treatment and was mitigated by ebselen co-treatment
Summary
Aminoglycoside (AG) antibiotics are the most prevalent treatment option for CF and other lifethreatening gram-negative bacterial infections (Flume et al, 2009; Drusano and Louie, 2011). Mouse Model Aminoglycoside-Induced Hyperacusis/Tinnitus more prevalent in clinical literature suggesting that AGinduced hearing loss is a serious concern for patients requiring treatments throughout life (American Speech-Language-Hearing Association [ASHA], 1994; Garinis et al, 2017). For these reasons, preclinical models are needed to understand the nature of AGinduced cochleotoxicity in order to develop solutions to prevent clinical auditory loss and dysfunction. It is unknown whether AG-induced inflammation can result in hyperacusis and tinnitus
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