Chronic excitotoxicity in the guinea pig cochlea induces temporary functional deficits without disrupting otoacoustic emissions

Prell, Colleen G. Le; Yagi, Minoru; Kawamoto, Kohei; Beyer, Lisa A.; Atkin, Graham; Raphael, Yehoash; Dolan, David F.; Bledsoe, Sanford C.; Moody, D. Branch

doi:10.1121/1.1772395

Cited by 36 publications

(31 citation statements)

References 63 publications

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“…Hearing loss has been associated with the swollen afferent dendrites under IHCs as in mice lacking the glutamate transporter GLAST after sound exposure, in chinchillas after kainic acid excitotoxicity, in guinea pigs after sound exposure, and after intra-cochlear infusion of the aminoglycoside antibiotic amikacin and the glutamate agonist AMPA (␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (Robertson, 1983;Zheng et al, 1997;Puel et al, 1998;Duan et al, 2000;Hakuba et al, 2000;Le Prell et al, 2004). Studies have also shown that functional recovery corresponds to structural recovery or reestablishment of the IHC/auditory-nerve synapse after acute excitotoxic-drug exposures (Zheng et al, 1997;Pujol and Puel 1999;X.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that noise-induced hearing loss may be caused, in part, by excitotoxicity of SGNs. The excitotoxic damage to SGN is suggested by massive swelling of afferent dendrites under IHCs (Liberman and Mulroy, 1982;Robertson, 1983;Puel et al, 1998;Le Prell et al, 2004). To further test the hypothesis that NFB activity plays an important role in maintaining Ca 2ϩ homeostasis and protecting SGNs from excitotoxic injury, we examined the expression of calcium-buffering proteins and the profile of afferent dendrites under IHCs in wild-type (WT) and p50 Ϫ/Ϫ mice.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear Factor κB Deficiency Is Associated with Auditory Nerve Degeneration and Increased Noise-Induced Hearing Loss

Lang¹,

Schulte²,

Zhou³

et al. 2006

J. Neurosci.

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Degeneration of the spiral ganglion neurons (SGNs) of the auditory nerve occurs with age and in response to acoustic injury. Histopathological observations suggest that the neural degeneration often begins with an excitotoxic process affecting the afferent dendrites under the inner hair cells (IHCs), however, little is known about the sequence of cellular or molecular events mediating this excitotoxicity. Nuclear factor B (NFB) is a transcription factor involved in regulating inflammatory responses and apoptosis in many cell types. NFB is also associated with intracellular calcium regulation, an important factor in neuronal excitotoxicity. Here, we provide evidence that NFB can play a central role in the degeneration of SGNs. Mice lacking the p50 subunit of NFB (p50 Ϫ/Ϫ mice) showed an accelerated hearing loss with age that was highly associated with an exacerbated excitotoxic-like damage in afferent dendrites under IHCs and an accelerated loss of SGNs. Also, as evidenced by immunostaining intensity, calcium-buffering proteins were significantly elevated in SGNs of the p50 Ϫ/Ϫ mice. Finally, the knock-out mice exhibited an increased sensitivity to low-level noise exposure. The accelerated hearing loss and neural degeneration with age in the p50 Ϫ/Ϫ mice occurred in the absence of concomitant hair cell loss and decline of the endocochlear potential. These results indicate that NFB activity plays an important role in protecting the primary auditory neurons from excitotoxic damage and age-related degeneration. A possible mechanism underlying this protection is that the NFB activity may help to maintain calcium homeostasis in SGNs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear Factor κB Deficiency Is Associated with Auditory Nerve Degeneration and Increased Noise-Induced Hearing Loss

Lang¹,

Schulte²,

Zhou³

et al. 2006

J. Neurosci.

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“…In the auditory system, auditory nerve degeneration may be a consequence of NTF deprivation that occurs when sensory cells in the organ of Corti are damaged. In the presence of intact hair cells, damaged auditory nerve peripheral processes will regrow and restore auditory sensation (Puel et al, 1991;Le Prell et al, 2004). However, with loss of hair cell targets, auditory nerve regrowth is minimal (Bohne and Harding, 1992;Strominger et al, 1995;Lawner et al, 1997;McFadden et al, 2004).…”

Section: Growth Factorsmentioning

confidence: 99%

“…The application of glutamate (Janssen et al, 1991) or glutamate agonists (Puel et al, 1991;Le Prell et al, 2004) results in functional deficits and swelling of auditory neurons equivalent to those observed after noise exposure (Robertson, 1983;Puel et al, 1998;Yamasoba et al, 2005). Large concentrations of glutamate are released in response to loud noise, and toxic concentrations of this excitatory amino acid lead to large sodium and potassium ion flux across the post-synaptic membranes and passive entry of chlorine; this osmotic imbalance results in entry of fluid into cells which in turn produces swelling, and ultimately, rupturing of cell membranes and degeneration (for review, see Le Prell et al, 2001).…”

Section: Glutamate Excitotoxicitymentioning

confidence: 99%

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

et al. 2007

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Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7-10 days following noise exposure, and one mechanism underlying noise-induced reduction in cochlear blood flow has finally been identified. These new insights have led to the formulation of new hypotheses regarding the molecular mechanisms of NIHL; and, from these, we have identified interventions that prevent NIHL, even with treatment onset delayed up to 3 days post-noise. It is essential to now assess the additive effects of agents intervening at different points in the cell death pathway to optimize treatment efficacy. Finding safe and effective interventions that attenuate NIHL will provide a compelling scientific rationale to justify human trials to eliminate this single major cause of acquired hearing loss.

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“…Threshold, tested separately for each ear, was defined as the lowest intensity of stimulation that yielded a repeatable waveform based on an identifiable ABR wave III or IV. ABR wave III is the most robust component of the guinea pig waveform [87,88].…”

Section: Auditory Brainstem Responsesmentioning

confidence: 99%

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Prell

Hughes

Miller

2007

Free Radical Biology and Medicine

198

188

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Free radical formation in the cochlea plays a key role in the development of noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant formation of both reactive oxygen species and reactive nitrogen species 7-10 days following noise exposure. Reduction in cochlear blood flow as a result of free radical formation has also been described. Here we report that the antioxidant agents, vitamins A, C, and E, act in synergy with magnesium to effectively prevent noise-induced trauma. Neither the antioxidant agents nor magnesium reliably reduced NIHL or sensory cell death with the doses we used when these agents were delivered alone. In combination, however, they were highly effective in reducing both hearing loss and cell death even with treatment initiated just one hour prior to noise exposure. This study supports roles for both free radical formation and noise-induced vasoconstriction in the onset and progression of NIHL. Identification of this safe and effective antioxidant intervention that attenuates NIHL provides a compelling rationale for human trials in which free radical scavengers are used to eliminate this single major cause of acquired hearing loss. Keywords cochlea; free radical; noise; hearing; antioxidant; vasodilation Mechanical destruction of cells in the organ of Corti was once assumed to be the primary cause of noise-induced hearing loss (NIHL) [1][2][3][4][5][6][7][8], with perhaps some effect of reduced blood flow to the inner ear [9][10][11][12][13][14][15][16][17][18]. We now know that another key factor is intense metabolic activity that results in production of excess free radicals [19][20][21][22][23] and lipid peroxidation products [24]. Noise-induced production of reactive oxygen species (ROS) in the cochlea has now been well characterized, and several recent reviews are available [25][26][27]. Mitochodrial dysfunction and ROS production have been implicated in numerous neurodegenerative syndromes and diseases [28-34, see 35,36]. The use of antioxidant agents holds significant therapeutic promise for many neurodegenerative processes [32,33,[37][38][39][40][41][42], and there is some suggestion that Correspondence to: C. G. Le Prell, Kresge Hearing Research Institute, University of Michigan, 1301 East Ann Street, Ann Arbor, MI 48109-0506, USA. Tel: +1-734-763-5104; fax +1-734-764-0014. E-mail address: colleeng@umich.edu. Disclosure. Dr. Miller is a founding member and Chairman of the Board of Directors at OtoMedicine, Inc., a company that has an option to license the intellectual property described in this report. Dr. Le Prell is a paid consultant to OtoMedicine, Inc. Drs. Miller and Le Prell have disclosed these relationships to the Medical School Conflict of Interest Board at the University of Michigan; conflict management plans including semi-annual review by the Board are in place.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publicatio...

show abstract

Chronic excitotoxicity in the guinea pig cochlea induces temporary functional deficits without disrupting otoacoustic emissions

Cited by 36 publications

References 63 publications

Nuclear Factor κB Deficiency Is Associated with Auditory Nerve Degeneration and Increased Noise-Induced Hearing Loss

Nuclear Factor κB Deficiency Is Associated with Auditory Nerve Degeneration and Increased Noise-Induced Hearing Loss

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

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