A Radical Demise: Toxins and Trauma Share Common Pathways in Hair Cell Death

Kopke, Richard D.; Allen, Keith; Henderson, Donald; Hoffer, Michael E.; Frenz, Dorothy A.; Water, Thomas Van De

doi:10.1111/j.1749-6632.1999.tb08641.x

Cited by 165 publications

(138 citation statements)

References 79 publications

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“…Whilst treatments exist for middle ear conditions, there are virtually no treatments that can ameliorate the damage to the inner ear and reduce the impact of sensorineural hearing loss. There is increasing evidence that oxidative stress and the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are key elements in the pathogenesis of cochlear injury due to noise exposure [3][4][5][6][7]. Compounds that target the mechanisms underlying oxidative stress thus offer considerable potential as therapies for hearing loss.…”

Section: Introductionmentioning

confidence: 99%

Adenosine amine congener mitigates noise-induced cochlear injury

Vlajkovic

Lee

Wong

et al. 2010

Purinergic Signalling

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Hearing loss from noise exposure is a leading occupational disease, with up to 5% of the population at risk world-wide. Here, we present a novel purine-based pharmacological intervention that can ameliorate noiseinduced cochlear injury. Wistar rats were exposed to narrow-band noise (8-12 kHz, 110 dB SPL, 2-24 h) to induce cochlear damage and permanent hearing loss. The selective adenosine A 1 receptor agonist, adenosine amine congener (ADAC), was administered intraperitoneally (100 µg/kg/day) at time intervals after noise exposure. Hearing thresholds were assessed using auditory brainstem responses and the hair cell loss was evaluated by quantitative histology. Free radical damage in the organ of Corti was assessed using nitrotyrosine immunohistochemistry. The treatment with ADAC after noise exposure led to a significantly greater recovery of hearing thresholds compared with controls. These results were upheld by increased survival of sensory hair cells and reduced nitrotyrosine immunoreactivity in ADAC-treated cochlea. We propose that ADAC could be a valuable treatment for noise-induced cochlear injury in instances of both acute and extended noise exposures.

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Section: Introductionmentioning

confidence: 99%

Adenosine amine congener mitigates noise-induced cochlear injury

Vlajkovic

Lee

Wong

et al. 2010

Purinergic Signalling

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“…New therapies for treatment of sensorineural hearing loss appear to be on the horizon, based on rapidly accumulating insight into the molecular signals involved in generating new hair cells [1,2], and on progress in understanding the molecular mechanisms associated with cochlear and auditory nerve degenerative processes (e.g., [3][4][5][6][7]; for review, see [7]). Agents have been identified that can minimize degeneration and facilitate repair [4,[8][9][10][11][12]14].…”

Section: Introductionmentioning

confidence: 99%

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Chen

Kujawa

McKenna

et al. 2005

Journal of Controlled Release

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Rapid progress in understanding the molecular mechanisms associated with cochlear and auditory nerve degenerative processes offers hope for the development of gene-transfer and molecular approaches to treat these diseases in patients. For therapies based on these discoveries to become clinically useful, it will be necessary to develop safe and reliable mechanisms for the delivery of drugs into the inner ear, bypassing the blood-labyrinthine barrier. Toward the goal of developing an inner ear perfusion device for human use, a reciprocating microfluidic system that allows perfusion of drugs into the cochlear perilymph through a single inlet hole in scala tympani of the basal turn was developed. The performance of a prototype, extracorporeal reciprocating perfusion system in guinea pigs is described. Analysis of the cochlear distribution of compounds after perfusion took advantage of the place-dependent generation of responses to tones along the length of the cochlea. Perfusion with a control artificial perilymph solution had no effect. Two drugs with wellcharacterized effects on cochlear physiology, salicylate (5 mM) and DNQX (6,7-Dinitroquinoxaline-2,3-dione; 100 and 300 μM), reversibly altered responses. The magnitude of drug effect decreased with distance from the perfusion pipette for up to 10 mm, and increased with dose and length of application.

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“…Noise and ototoxic chemicals may lead to a precocious, rapid hearing loss, whereas aging leads to a more insidious, chronic loss of hearing. Research over the last decades has identified reactive oxygen species (ROS) 1 as the major factor mediating hearing loss (1). ROS is generated within the cochlea after exposure to ototoxic drugs (e.g.…”

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confidence: 99%

NOX3, a Superoxide-generating NADPH Oxidase of the Inner Ear

Bánfi

Malgrange

Knisz³

et al. 2004

Journal of Biological Chemistry

402

349

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Reactive oxygen species (ROS) play a major role in drug-, noise-, and age-dependent hearing loss, but the source of ROS in the inner ear remains largely unknown. Herein, we demonstrate that NADPH oxidase (NOX) 3, a member of the NOX/dual domain oxidase family of NADPH oxidases, is highly expressed in specific portions of the inner ear. As assessed by real-time PCR, NOX3 mRNA expression in the inner ear is at least 50-fold higher than in any other tissues where its expression has been observed (e.g. fetal kidney, brain, skull). Microdissection and in situ hybridization studies demonstrated that NOX3 is localized to the vestibular and cochlear sensory epithelia and to the spiral ganglions. Transfection of human embryonic kidney 293 cells with NOX3 revealed that it generates low levels of ROS on its own but produces high levels of ROS upon co-expression with cytoplasmic NOX subunits. NOX3-dependent superoxide production required a stimulus in the absence of subunits and upon co-expression with phagocyte NADPH oxidase subunits p47 phox and p67 phox , but it was stimulus-independent upon co-expression with colon NADPH oxidase subunits NOX organizer 1 and NOX activator 1. Pre-incubation of NOX3-transfected human embryonic kidney 293 cells with the ototoxic drug cisplatin markedly enhanced superoxide production, in both the presence and the absence of subunits. Our data suggest that NOX3 is a relevant source of ROS generation in the cochlear and vestibular systems and that NOX3-dependent ROS generation might contribute to hearing loss and balance problems in response to ototoxic drugs.The inner ear is a highly complex structure involved in hearing and balancing. The conversion of sound into electrical signals occurs within the cochlea, in the organ of Corti, and the electrical signals are conducted by the axons of spiral ganglion neurons to the brain. The linear movement of the head is sensed by the otolith organs (utricle and saccule) and the rotation movements by the ampulla of the semicircular canals. The signals generated in the vestibular system are transmitted by the vestibular ganglion neurons to the central nervous system.Hearing impairment caused by loss of cochlear function occurs frequently, if not invariably, over a lifetime. Noise and ototoxic chemicals may lead to a precocious, rapid hearing loss, whereas aging leads to a more insidious, chronic loss of hearing. Research over the last decades has identified reactive oxygen species (ROS) 1 as the major factor mediating hearing loss (1). ROS is generated within the cochlea after exposure to ototoxic drugs (e.g. cisplatin (2, 3), aminoglycoside antibiotics (3)) or to noise (4). Signs of oxidative stress, such as DNA damage and lipid peroxidation, have been documented in vivo in response to those challenges (5, 6), as well as in cochlear aging (7). The vestibular system is also damaged by ototoxic drugs (8, 9) in a process that includes excessive ROS production (10, 11).Although the role of oxidative stress in inner ear damage is well established, its source ...

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A Radical Demise: Toxins and Trauma Share Common Pathways in Hair Cell Death

Cited by 165 publications

References 79 publications

Adenosine amine congener mitigates noise-induced cochlear injury

Adenosine amine congener mitigates noise-induced cochlear injury

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

NOX3, a Superoxide-generating NADPH Oxidase of the Inner Ear

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