A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

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.

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

“…Additionally, these abnormal behaviors occur in the presence of only a mild loss of hearing sensitivity. These new findings are consistent with prior findings that amikacin can cause these behavioral symptoms following a mild threshold shift, although the mechanism will need to be elucidated (Longenecker et al, 2020; Figure 7). The largest difference between the two studies was that tobramycin treated mice demonstrated less startle magnitude increases after treatment than amikacin treated mice (Figure 5 vs.…”

“…A similar finding was observed with the clinically modified or adopted responder criteria (American Speech-Language-Hearing Association, 1994). This finding was comparable to the effect of ebselen on amikacin treated mice (Longenecker et al, 2020), and provides evidence that ebselen or other otoprotective drugs might work at ameliorating AG-induced hearing loss in clinic (Avci et al, 2016;Fox et al, 2016;Dogan et al, 2017;El-Anwar et al, 2018;Apaydin et al, 2021). However, the threshold shifts seen here were drastically different than those found with a similar tobramycin dosing experiment in Swiss-Webster mice (Gu et al, 2020).…”

“…several strains of mice (Bullock et al, 1997;Pilz et al, 2014;Longenecker et al, 2018). This fact amplifies the importance of the odd behavioral shift towards dramatic increases in startle magnitude seen in some tobramycin (Figures 4A,B), and amikacin treated mice (Longenecker et al, 2020). The main reason hyperacusis was not observed in group averages of tobramycin treated mice (Figure 5) is because most mice did not develop hyperacusis and habituated to the startle (Figures 4D, 5F), which therefore decreased the average startle magnitude (Figures 5A-E).…”

“…The largest difference between the two studies was that tobramycin treated mice demonstrated less startle magnitude increases after treatment than amikacin treated mice (Figure 5 vs. Figure 6 from Longenecker et al, 2020). This was especially true at the early epochs following treatment (Figures 5A-C).…”

“…However, it is important to note that hyperacusis manifested differently between mice. Increased input/output startle functions such as the presented example of tobramycin treated mouse M94 (Figure 4A) was more commonly observed in amikacin treated mice (Longenecker et al, 2020). M94 demonstrated consistent hyperacusis throughout the testing period while F305 only experienced hyperacusis at weeks 2 and 10 after the start of dosing followed with clear habituation the rest of the epochs ( Figures 4A,B).…”