Dataset Information

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.

SUBMITTER: Longenecker RJ

PROVIDER: S-EPMC7530258 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus.

Longenecker Ryan J RJ Gu Rende R Homan Jennifer J Kil Jonathan J

Frontiers in neuroscience 20200918

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 sensit ...[more]

PMID: 33041759

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Project description:Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.

Project description:Although tinnitus represents a major global burden, no causal therapy has yet been established. Ongoing controversies about the neuronal pathophysiology of tinnitus hamper efforts in developing advanced therapies. Hypothesizing that the unnoticed co-occurrence of hyperacusis and differences in the duration of tinnitus may possibly differentially influence the neural correlate of tinnitus, we analyzed 33 tinnitus patients without (T-group) and 20 tinnitus patients with hyperacusis (TH-group). We found crucial differences between the T-group and the TH-group in the increase of annoyance, complaints, tinnitus loudness, and central neural gain as a function of tinnitus duration. Hearing thresholds did not differ between T-group and TH-group. In the TH-group, the tinnitus complaints (total tinnitus score) were significantly greater from early on and the tinnitus intensity distinctly increased over time from ca. 12 to 17 dB when tinnitus persisted more than 5 years, while annoyance responses to normal sound remained nearly constant. In contrast, in the T-group tinnitus complaints remained constant, although the tinnitus intensity declined over time from ca. 27 down to 15 dB beyond 5 years of tinnitus persistence. This was explained through a gradually increased annoyance to normal sound over time, shown by a hyperacusis questionnaire. Parallel a shift from a mainly unilateral (only 17% bilateral) to a completely bilateral (100%) tinnitus percept occurred in the T-group, while bilateral tinnitus dominated in the TH-group from the start (75%). Over time in the T-group, ABR wave V amplitudes (and V/I ratios) remained reduced and delayed. By contrast, in the TH-group especially the ABR wave III and V (and III/I ratio) continued to be enhanced and shortened in response to high-level sound stimuli. Interestingly, in line with signs of an increased co-occurrence of hyperacusis in the T-group over time, ABR wave III also slightly increased in the T-group. The findings disclose an undiagnosed co-occurrence of hyperacusis in tinnitus patients as a main cause of distress and the cause of complaints about tinnitus over time. To achieve urgently needed and personalized therapies, possibly using the objective tools offered here, a systematic sub-classification of tinnitus and the co-occurrence of hyperacusis is recommended.

Dataset Information

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus.

Publications

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus.

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