Apoptotic death of hair cells in mammalian vestibular sensory epithelia

Forge, Andrew; Lin, Longnian

doi:10.1016/s0378-5955(99)00177-x

Cited by 191 publications

(176 citation statements)

References 45 publications

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“…It is worth noting, however, that gentamicin exposure is reported to induce hair cell loss within 6 h in utricular cultures and within 18-24 h following intratympanic application in vivo (Forge and Li 2000;Suzuki et al 2008). In addition, preliminary studies in guinea pigs demonstrate that cochlear perfusion of neomycin leads to rapid hair cell loss (60-90 min;Wang et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Aminoglycoside ototoxicity likely involves activation of several cell death pathways, as morphological features of both apoptotic-like and non-apoptotic modes of cell death are visible in a single sensory organ (Li et al 1995;Forge and Li 2000;Owens et al 2007;Taylor et al 2008). Caspase inhibition protects hair cells from neomycin toxicity in the mouse utricle in vitro and from gentamicin otoxicity in chick in vivo, suggesting that activation of classical apoptotic-like pathways may lead to hair cell death in some tissues or species Cunningham et al 2002;Matsui et al 2003;Kaiser et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

102

116

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Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

102

116

View full text Add to dashboard Cite

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“…[3][4][5][6] Caspase-3 plays a central role in the execution phase of classic apoptosis by cleaving poly (ADP-ribose) polymerase (PARP1), a 113 kDa nuclear repair enzyme, into fragments of 89 and 24 kDa. 7,8 Caspase-3 can be activated by cytochrome c released from mitochondria upon loss of mitochondrial membrane potential, 9 an event that has been implicated in aminoglycoside-mediated hair cell death in organ cultures.…”

Section: Introductionmentioning

confidence: 99%

Caspase-independent pathways of hair cell death induced by kanamycin in vivo

et al. 2005

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Cochlear and vestibular sensory cells undergo apoptosis when exposed to aminoglycoside antibiotics in organ culture, but mechanisms of chronic drug-induced hair cell loss in vivo are unclear. We investigated cell death pathways in a mouse model of progressive kanamycin-induced hair cell loss. Hair cell nuclei showed both apoptotic-and necrotic-like appearances but markers for classic apoptotic pathways (cytochrome c, caspase-9, caspase-3, JNK, TUNEL) were absent. In contrast, drug treatment caused EndoG translocation, activation of l-calpain, and both the synthesis and activation of cathepsin D. Poly (ADP-ribose) polymerase 1 (PARP1) was decreased, but a caspase-derived 89 kDa PARP1 fragment was not present. The mRNA level of PARP1 remained unchanged. Thus, chronic administration of aminoglycosides causes multiple forms of cell death, without a major contribution by classic apoptosis. These results provide a better understanding of the toxic effects of aminoglycosides and are relevant to design protection from aminoglycosideinduced hearing loss.

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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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Apoptotic death of hair cells in mammalian vestibular sensory epithelia

Cited by 191 publications

References 45 publications

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Caspase-independent pathways of hair cell death induced by kanamycin in vivo

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

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