Caspase Inhibitors Promote Vestibular Hair Cell Survival and Function after Aminoglycoside Treatment<i>In Vivo</i>

Matsui, Jonathan I.; Haque, Asim; Huss, David; Messana, Elizabeth; Alosi, Julie A.; Roberson, David W.; Cotanche, Douglas A.; Dickman, J. David; Warchol, Mark E.

doi:10.1523/jneurosci.23-14-06111.2003

Cited by 94 publications

(76 citation statements)

References 60 publications

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“…The primary disadvantage of in vitro model systems is that they may not accurately predict the in vivo condition. However, in vivo experiments in both birds (Cheng et al, 2003;Matsui et al, 2004;Matsui et al, 2003) and mammals (Okuda et al, 2005;Pirvola et al, 2000;Wang et al, 2003a;Ylikoski et al, 2002) indicate that the mechanism(s) underlying aminoglycoside-induced hair cell death are similar to those that have been reported for the mouse utricle preparation in vitro. Still, there may be differences in the mechanisms underlying ototoxicity in vivo and in vitro (Jiang et al, 2005).…”

Section: Discussionsupporting

confidence: 63%

“…Second, the hair cells of the mouse utricle are sensitive to death from exposure to the same therapeutic drugs that kill cochlear hair cells (Cunningham et al, 2002;Zhang et al, 2003). Third, the cellular mechanisms mediating ototoxic hair cell death appear to be similar for both utricular hair cells in vitro and cochlear hair cells in vivo (Cunningham et al, 2002;Forge and Li, 2000;Liu et al, 1998;Mangiardi et al, 2004;Matsui et al, 2003;Matsui et al, 2002;Nakagawa et al, 2003;Pirvola et al, 2000;Ylikoski et al, 2002). Finally, the use of mouse tissue allows for examination of the effects of specific gene products through the utilization of tissue from transgenic and knockout animals (Cunningham et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The adult mouse utricle as an in vitro preparation for studies of ototoxic-drug-induced sensory hair cell death

Cunningham

2006

Brain Research

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Sensory hair cells of the inner ear are susceptible to death from a variety of stresses including aging, noise trauma, genetic disorders, and exposure to certain therapeutic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. This is a short technical report describing the dissection and culture of the adult mouse utricle. This in vitro preparation allows for detailed studies of ototoxic drug-induced hair cell death in an adult mammalian system. In addition, this preparation allows for examination of the effects of specific gene products through the use of transgenic and knockout mouse models.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

The adult mouse utricle as an in vitro preparation for studies of ototoxic-drug-induced sensory hair cell death

Cunningham

2006

Brain Research

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“…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). In vivo experiments in rats and zebrafish (Danio rerio), however, reveal evidence for caspase-independent hair cell death (Jiang et al 2006;Coffin et al 2013), suggesting that alternative cell death pathways may be involved.…”

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

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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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“…In recent years, significant progress has been made in characterizing aminoglycoside-induced hair cell death. Several studies show both molecular and morphological evidence that ototoxic hair cell death is apoptotic (Lang and Liu 1997;Forge and Li 2000;Cunningham et al 2002;Matsui et al 2002Matsui et al , 2003Cheng et al 2003;Mangiardi et al 2004;Eshraghi et al 2007). Aminoglycosides lead to the activation of caspases, and broad-spectrum caspase inhibitors suppress aminoglycoside-induced hair cell death (Cunningham et al 2002;Matsui et al 2002Matsui et al , 2003Cheng et al 2003;Tabuchi et al 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies show both molecular and morphological evidence that ototoxic hair cell death is apoptotic (Lang and Liu 1997;Forge and Li 2000;Cunningham et al 2002;Matsui et al 2002Matsui et al , 2003Cheng et al 2003;Mangiardi et al 2004;Eshraghi et al 2007). Aminoglycosides lead to the activation of caspases, and broad-spectrum caspase inhibitors suppress aminoglycoside-induced hair cell death (Cunningham et al 2002;Matsui et al 2002Matsui et al , 2003Cheng et al 2003;Tabuchi et al 2007). In addition, in both the auditory and vestibular systems, inhibition of the JNK signaling pathway has been shown to protect hair cells against aminoglycoside-induced death (Pirvola et al 2000;Ylikoski et al 2002;Matsui et al 2004;Sugahara et al 2006;Eshraghi et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Taleb

Brandon

Lee

et al. 2008

JARO

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Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including cJun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) is a highly conserved stress response that can inhibit JNK-and caspasedependent apoptosis in a variety of systems. We have previously shown that heat shock results in a robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin-and aminoglycoside-induced hair cell death. In our system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Therefore, we have begun to examine the role of Hsp70 in mediating the protective effect of heat shock. To determine whether Hsp70 is necessary for the protective effect of heat shock against aminoglycoside-induced hair cell death, we utilized utricles from Hsp70.1/3 −/− mice. While heat shock inhibited gentamicin-induced hair cell death in wild-type utricles, utricles from Hsp70.1/3 −/− mice were not protected. In addition, we have examined the role of the major heat shock transcription factor, Hsf1, in mediating the protective effect of heat shock. Utricles from Hsf1 −/− mice and wild-type littermates were exposed to heat shock followed by gentamicin. The protective effect of heat shock on aminoglycoside-induced hair cell death was only observed in wildtype mice and not in Hsf1 −/− mice. To determine whether Hsp70 is sufficient to protect hair cells, we have utilized transgenic mice that constitutively overexpress Hsp70. Utricles from Hsp70-overexpressing mice and wild-type littermates were cultured in the presence of varying neomycin concentrations for 24 h. The Hsp70-overexpressing utricles were significantly protected against neomycin-induced hair cell death at moderate to high doses of neomycin. This protective effect was achieved without a heat shock. Taken together, these data indicate that Hsp70 and Hsf1 are each necessary for the protective effect of heat shock against aminoglycoside-induced death. Furthermore, overexpression of Hsp70 alone significantly inhibits aminoglycoside-induced hair cell death.

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Caspase Inhibitors Promote Vestibular Hair Cell Survival and Function after Aminoglycoside TreatmentIn Vivo

Cited by 94 publications

References 60 publications

The adult mouse utricle as an in vitro preparation for studies of ototoxic-drug-induced sensory hair cell death

The adult mouse utricle as an in vitro preparation for studies of ototoxic-drug-induced sensory hair cell death

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

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

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