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

Abstract

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.

L-type calcium channel blockade with verapamil prevents noise induced neuronal dys-synchrony

“…To assess temporal auditory processing, giASRs are evaluated (i.e., the subconscious response of an awake behaving animal in response to a startling sound preceded by a silent gap embedded in a noise) (English & Drummond, 2021;Fournier & Hebert, 2016;Ison et al, 1991;Kodsi & Swerdlow, 1995;Lobarinas et al, 2013;Sebo et al, 2020;Shi et al, 2022;Sun et al, 2011;Weible et al, 2020).In line with previous studies, inhibition of the acoustic startle reflex (ASR) is observed in the presence of a silent gap (Fournier & Hebert, 2016Galazyuk & Hebert, 2015;Longenecker et al, 2021;Moreno-Paublete et al, 2017;Weible et al, 2020;Wilson et al, 2019). This inhibition of the ASR is not diminished following noise exposure, calcium channel blockade or combination of both (Fig.…”

Unveiling the Role of Oxidative Stress in Cochlear Hair Cell Death: Prospective Phytochemical Therapeutics against Sensorineural Hearing Loss

“…Tobramycin, an aminoglycoside, is commonly used long-term to help treat cystic fibrosis-associated pulmonary bacterial infections [106]. Unfortunately, tobramycin is known to induce ototoxicity [107,108]. Gu and colleagues, however, demonstrated that mice co-treated with ebselen are able to alleviate tobramycin-induced ototoxicity of the cochlea and co-treated cochlear explants were observed to have reduced tobramycin-induced hair cell loss [105].…”

Modulation der akustisch evozierten Schreckreaktion durch Präpulse und deren Anwendung zur Bestimmung reflexbasierter Unterscheidungsschwellen

“…Borg, 1982;Overbeck und Church, 1992;Popelar et al, 2008;Alvarado et al, 2012;Möhrle et al, 2019;Kiefer et al, 2022;Koch et al, 2022), ( 2) Mäuse (z.B. Henry, 1979;Kujawa und Liberman, 2009;Hickox und Liberman, 2014;Nowotny et al, 2017;Cederroth et al, 2019;Longenecker et al, 2021;Kiefer et al, 2022), (3) Mongolische Wüstenrennmäuse (z.B. Nowotny et al, 2011;Kiefer et al, 2015;Wrobel et al, 2018;Tziridis et al, 2021;Kiefer et al, 2022), (4) Hamster (z.B.…”