Otoprotective Properties of Mannitol Against Gentamicin Induced Hair Cell Loss

Wood, John W.; Bas, Esperanza; Gupta, Chhavi; Selman, Yamil; Eshraghi, Adrien A.; Telischi, Fred F.; Water, Thomas R. Van De

doi:10.1097/mao.0000000000000342

Cited by 19 publications

(12 citation statements)

References 23 publications

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“…As expected, gentamicin-induced ototoxicity on OHCs was higher in the basal than in the middle or apical turns ( fig. 3 , table 1 ) as described in other studies [Cunningham et al, 2011;McDowell, 1982;Wood et al, 2014]. Our findings are in line with data obtained in auditory cell lines.…”

Section: Metformin Protects Hcs From Gentamicin-induced Toxicitysupporting

confidence: 83%

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Glutz¹,

Leitmeyer²,

Setz³

et al. 2015

Audiol Neurotol

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Metformin is a commonly used antidiabetic drug. It has been shown that this drug activates the AMP-activated protein kinase, which inhibits downstream the mammalian target of rapamycin. In addition, several studies indicate that metformin reduces intracellular reactive oxygen species. Our data, using an in vitro rat model, indicate that metformin is able to protect auditory hair cells (HCs) from gentamicin-induced apoptotic cell death. Moreover, metformin has no toxic effect on spiral ganglion neuronal survival or outgrowth in vitro. These results suggest a protective effect of metformin on auditory HC survival in gentamicin-induced HC loss in vitro.

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Section: Metformin Protects Hcs From Gentamicin-induced Toxicitysupporting

confidence: 83%

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Glutz¹,

Leitmeyer²,

Setz³

et al. 2015

Audiol Neurotol

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“…These findings support the hypothesis that VS-induced SNHL may result in part from TNF-α-containing tumor secretions passing into the cochlea via the internal auditory canal. The hypothesis that TNF-α may play a role in VS-induced SNHL comes from several studies showing that (a) VS tumor secretions contain high levels of TNF-α (20), (b) VS tumor size and proximity to the inner ear are poorly correlated with SNHL in VS patients (3), and (c) upregulation of TNF-α in the cochlea in response to a variety of etiologies of inner ear disease causes hearing loss (21)(22)(23)(24)(25)(42)(43)(44)(45)(46). Previous studies have shown upregulated levels of TNF-α following exposure to high levels of noise, implicating TNF-α in acoustic trauma (24,25,46).…”

Section: Discussionmentioning

confidence: 99%

“…Direct inoculation of cerebrospinal fluid with Streptococcus pneumoniae in Mongolian gerbil model led to an increase in TNF-α circulation that was directly associated with bacterial meningitis and elevations in auditory brainstem response (ABR) thresholds (23). Activation of TNFα is also observed in rodents treated with cisplatin (42,43) and gentamicin (44,45), both of which have known structural and functional ototoxic effects. Our findings contribute to this body of work by suggesting that the acute effects of TNF-α exposure on cochlear structure and function may be specific to synaptic degeneration and reduction in CAP amplitudes, respectively.…”

Section: Discussionmentioning

confidence: 99%

Intracochlear Perfusion of Tumor Necrosis Factor-Alpha Induces Sensorineural Hearing Loss and Synaptic Degeneration in Guinea Pigs

et al. 2020

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Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that plays a prominent role in the nervous system, mediating a range of physiologic and pathologic functions. In the auditory system, elevated levels of TNF-α have been implicated in several types of sensorineural hearing loss, including sensorineural hearing loss induced by vestibular schwannoma, a potentially fatal intracranial tumor that originates from the eighth cranial nerve; however, the mechanisms underlying the tumor's deleterious effects on hearing are not well-understood. Here, we investigated the effect of acute elevations of TNF-α in the inner ear on cochlear function and morphology by perfusing the cochlea with TNF-α in vivo in guinea pigs. TNF-α perfusion did not significantly change thresholds for compound action potential (CAP) responses, which reflect cochlear nerve activity, or distortion product otoacoustic emissions, which reflect outer hair cell integrity. However, intracochlear TNF-α perfusion reduced CAP amplitudes and increased the number of inner hair cell synapses without paired post-synaptic terminals, suggesting a pattern of synaptic degeneration that resembles that observed in primary cochlear neuropathy. Additionally, etanercept, a TNF-α blocker, protected against TNF-α-induced synaptopathy when administered systemically prior to intracochlear TNF-α perfusion. Findings motivate further investigation into the harmful effects of chronically elevated intracochlear levels of TNF-α, and the potential for etanercept to counter these effects.

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“…This may represent a very small quantity of fluid flow across the perforation despite no noticeable change in donor or receptor volumes during the experiment. If we assume ototoxicity from aminoglycosides applied directly to hair cells occurs with 10μM of compound (a documented ototoxic dose in explanted hair cells) then with the dosing regimen seen in this experiment applied to the RWM, an intact membrane would require 7 days to diffuse 10μM across the RWM while a membrane with a single microperforation of approximately 2.5 × 10 -3 mm 2 would require just under 5 hours 29 . Assuming minimal interaction between perforations, an increase in the number of perforations will inversely decrease the time necessary to achieve a target dose.…”

Section: Discussionmentioning

confidence: 99%

Microperforations Significantly Enhance Diffusion Across Round Window Membrane

Kelso¹,

Watanabe²,

Wazen³

et al. 2015

Otology &Amp; Neurotology

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Hypothesis Introduction of microperforations in round window membrane (RWM) will allow reliable and predictable intracochlear delivery of pharmaceutical, molecular or cellular therapeutic agents. Background Reliable delivery of medications into the inner ear remains a formidable challenge. The RWM is an attractive target for intracochlear delivery. However, simple diffusion across intact RWM is limited by what material can be delivered, size of material to be delivered, difficulty with precise dosing, timing, and precision of delivery over time. Further, absence of reliable methods for measuring diffusion across RWM in vitro is a significant experimental impediment. Methods A novel model for measuring diffusion across guinea pig RWM, with and without microperforation, was developed and tested: cochleae, sparing the RWM, were embedded in 3D-printed acrylic holders using hybrid dental composite and light cured to adapt the round window niche to 3ml Franz diffusion cells. Perforations were created with 12.5μm diameter needles and examined with light microscopy. Diffusion of 1mM Rhodamine B across RWM in static diffusion cells was measured via fluorescence microscopy. Results The diffusion cell apparatus provided reliable and replicable measurements of diffusion across RWM. The permeability of Rhodamine B across intact RWM was 5.1 × 10-9 m/s. Manual application of microperforation with a 12.5μm diameter tip produced an elliptical tear removing 0.22±0.07% of the membrane and was associated with a 35x enhancement in diffusion (p<0.05). Conclusion Diffusion cells can be applied to the study of RWM permeability in vitro. Microperforation in RWM is an effective means of increasing diffusion across the RWM.

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Otoprotective Properties of Mannitol Against Gentamicin Induced Hair Cell Loss

Cited by 19 publications

References 23 publications

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Intracochlear Perfusion of Tumor Necrosis Factor-Alpha Induces Sensorineural Hearing Loss and Synaptic Degeneration in Guinea Pigs

Microperforations Significantly Enhance Diffusion Across Round Window Membrane

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