Intravenously delivered aminoglycoside antibiotics, tobramycin and amikacin, are not ototoxic in mice

Ogier, Jacqueline M.; Lockhart, Paul J.; Burt, Rachel

doi:10.1016/j.heares.2019.107870

Cited by 12 publications

(12 citation statements)

References 120 publications

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“…In an in vivo aminoglycoside mouse model, we found that amikacin can induce mild temporary ABR threshold shifts that fluctuate over a 3-4-month time period (Figure 2). These results are similar to the reported observation from other recent aminoglycoside experiments (Murillo-Cuesta et al, 2010;Ogier et al, 2020). The percentage of ears that showed clinically relevant hearing loss was minimal and concentrated at times closest to the amikacin treatment and gradually diminished to near baseline levels by week 14 (Figure 2 and Table 1; American Speech-Language-Hearing Association [ASHA], 1994;Gu et al, 2020).…”

Section: Temporary Threshold Shifts In the Absence Of Detectable Hairsupporting

confidence: 88%

“…One recent study also showed minor threshold shifts with minimal hair cell loss following treatment with both amikacin and tobramycin in mice. This is also a common finding in the literature when clinically comparable doses of AGs are used (Ogier et al, 2020). We did not observe any detectable loss of SGNs (Supplementary Figure 1), or ribbon synapses (Figure 4).…”

Section: Temporary Threshold Shifts In the Absence Of Detectable Hairsupporting

confidence: 84%

“…However, our rates may have been higher if more ABR frequencies were tested, which needs to be examined in future studies. In general, most mice strains have shown low levels of cochleotoxic change that correspond well to human studies (Ogier et al, 2020). However, most of animal studies utilized one dose of AG, which does not correlate to the cumulative effects of AG-induced cochleotoxicity seen in CF patients receiving AG treatment throughout life (Garinis et al, 2017).…”

Section: Temporary Threshold Shifts In the Absence Of Detectable Hairmentioning

confidence: 76%

“…Animal models have demonstrated varying degrees of AG-induced cochlear hair cell damage and subsequent hearing loss ( Huth et al, 2011 ; Ogier et al, 2020 ). However, emerging evidence suggests that SGNs, and their specialized ribbon synapses may also be damaged by AGs ( Sone et al, 1998 ; Pauna et al, 2017 ; Hong et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…The goals for this study were to develop an amikacin-induced auditory loss and dysfunction mouse model. First, we investigated if a clinically relevant dosing schedule of amikacin led to hearing loss ( Ogier et al, 2020 ). Hearing functionality was assessed via changes in ABR thresholds and ABR wave amplitudes ( Gu et al, 2012 ; Lowe and Walton, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

Longenecker¹,

Gu²,

Homan³

et al. 2020

Front. Neurosci.

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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.

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Section: Temporary Threshold Shifts In the Absence Of Detectable Hairsupporting

confidence: 88%

Section: Temporary Threshold Shifts In the Absence Of Detectable Hairsupporting

confidence: 84%

Section: Temporary Threshold Shifts In the Absence Of Detectable Hairmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

Longenecker¹,

Gu²,

Homan³

et al. 2020

Front. Neurosci.

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ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death

et al. 2022

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Aminoglycoside antibiotics are lifesaving medicines, crucial for the treatment of chronic or drug resistant infections. However, aminoglycosides are toxic to the sensory hair cells in the inner ear. As a result, aminoglycoside-treated individuals can develop permanent hearing loss and vestibular impairment. There is considerable evidence that reactive oxygen species (ROS) production and the subsequent phosphorylation of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) drives apoptosis in aminoglycoside-treated hair cells. However, treatment strategies that directly inhibit ROS, JNK, or P38 are limited by the importance of these molecules for normal cellular function. Alternatively, the upstream regulator apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) is a key mediator of ROS-induced JNK and P38 activation under pathologic but not homeostatic conditions. We investigated ASK1 as a mediator of drug-induced hair cell death using cochlear explants from Ask1 knockout mice, demonstrating that Ask1 deficiency attenuates neomycin-induced hair cell death. We then evaluated pharmacological inhibition of ASK1 with GS-444217 as a potential otoprotective therapy. GS-444217 significantly attenuated hair cell death in neomycin-treated explants but did not impact aminoglycoside efficacy against P. aeruginosa in the broth dilution test. Overall, we provide significant pre-clinical evidence that ASK1 inhibition represents a novel strategy for preventing aminoglycoside ototoxicity. Key messages • ASK1 is an upstream, redox-sensitive regulator of P38 and JNK, which are known mediators of hair cell death. • Ask1 knockout does not affect hair cell development in vivo, but significantly reduces aminoglycoside-induced hair cell death in vitro. • A small-molecule inhibitor of ASK1 attenuates neomycin-induced hair cell death, and does not impact antibiotic efficacy in vitro. • ASK1 may be a novel molecular target for preventing aminoglycoside-induced hearing loss.

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Suppression of delayed rectifier K+ channels by gentamicin induces membrane hyperexcitability through JNK and PKA signaling pathways in vestibular ganglion neurons

Zhang

Wang

et al. 2021

Biomedicine & Pharmacotherapy

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Intravenously delivered aminoglycoside antibiotics, tobramycin and amikacin, are not ototoxic in mice

Cited by 12 publications

References 120 publications

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death

Suppression of delayed rectifier K+ channels by gentamicin induces membrane hyperexcitability through JNK and PKA signaling pathways in vestibular ganglion neurons

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