Neural Plasticity

Neural Plasticity / 2021 / Article
Special Issue

Reestablishing Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells for Hearing Loss 2020

View this Special Issue

Review Article | Open Access

Volume 2021 |Article ID 4909237 | https://doi.org/10.1155/2021/4909237

Peng Wu, Xianmin Wu, Chunhong Zhang, Xiaoyun Chen, Yideng Huang, He Li, "Hair Cell Protection from Ototoxic Drugs", Neural Plasticity, vol. 2021, Article ID 4909237, 9 pages, 2021. https://doi.org/10.1155/2021/4909237

Hair Cell Protection from Ototoxic Drugs

Academic Editor: Geng lin Li
Received29 Mar 2020
Accepted28 Jun 2021
Published12 Jul 2021

Abstract

Hearing loss is often caused by death of sensory hair cells (HCs) in the inner ear. HCs are vulnerable to some ototoxic drugs, such as aminoglycosides(AGs) and the cisplatin.The most predominant form of drug-induced cell death is apoptosis. Many efforts have been made to protect HCs from cell death after ototoxic drug exposure. These mechanisms and potential targets of HCs protection will be discussed in this review.And we also propose further investigation in the field of HCs necrosis and regeneration, as well as future clinical utilization.

1. Introduction

Hearing loss is the most common sensory impairment in humans. It is estimated that there were 466 million people living with hearing loss in 2018 [1]. Hearing loss is often caused by death of sensory hair cells (HCs) in the inner ear, which function in transducing the sound waves into electric signals [26]. HCs are vulnerable to a variety of different stresses, such as aging, acoustic trauma, genetic disorders, infection, and exposure to some ototoxic drugs [713]. Unfortunately, the mammals only have very limited HC regeneration ability, and the death of HCs in mammals is irreversible, thus leading to permanent hearing deficit [1318]. Although hearing loss is not a life-threatening disease, it can affect the patient’s quality of life, especially in children, which will cause delays in language acquisition and dumb. That will cause significant burden on families and society.

Currently, the most effective and convenient protection is avoiding exposure to known ototoxic drugs. Although there are several drugs that can injure HCs, the most commonly encountered ototoxic drugs are the aminoglycosides (AGs) and the antineoplastic agent cisplatin. AGs are the most commonly prescribed antibiotics, such as gentamicin, amikacin, kanamycin, and neomycin, which are usually used in the treatment of infections caused by aerobic gram-negative bacteria. Cisplatin is a platinum-based chemotherapeutic drug, which is often used for the chemotherapy of malignant tumors. But the ototoxicity limits the clinical application of these two kinds of drugs. Both AGs and cisplatin can induce apoptotic cell death in HCs, especially the outer HCs of the basal turn [9, 1923].

HCs can undergo cell death through apoptosis and necrosis. But the most predominant form of drug-induced cell death is apoptosis. In order to protect HCs from ototoxic insult, a better understanding of the mechanisms of aminoglycoside- and cisplatin-induced hair cell death is required. Current studies of these apoptotic cell death mechanisms and potential targets of HC protection are discussed in this review.

2. Mechanism and Protection

2.1. Route of Ototoxic Drugs into Hair Cells

After systemic administration, ototoxic drugs can pass the blood-labyrinth barrier (BLB) and enter the endolymph via the Reissner’s membrane, especially via the stria vascularis [24]. After that, they enter into HCs and cause cell death.

Multiple pathways for entry of AGs and cisplatin into HCs exist. One pathway is endocytosis at the apical and synaptic poles of HCs, although direct evidence for its involvement in cytotoxicity has not been found [25, 26]. Transport through ion channels, especially mechanoelectrical transducer (MET) channel, is supposed to play an important role in AGs uptake into HCs [2528]. Some researchers suggest AGs and cisplatin can enter the HCs through MET channel [25, 29, 30] or Copper Transporter 1 (CTR1) [31], respectively, which are located at the top of hair cell stereocilia. Other studies suggest that MET channel is also a major contributor to the entry of cisplatin into HCs, at least in the zebrafish [32, 33]. But a direct interaction between cisplatin and mammalian MET channels has not been reported. Some researchers reveal that cisplatin entry into cochlear and HCs is also mediated by organic cation transporter (OCT), and the expression of OCT2, an isoforms of OCT, has been detected in HCs, as well as in stria vascularis [31, 34]. There is also evidence for the participation of transient receptor potential (TRP) channels, a family of polymodal ion channels activated by a variety of physical and chemical stimulation, such as oxidative stress, tissue damage, and inflammation [28]. TRP channels, such as TRPA1, TRPV1, and TRPV4, are additional candidate aminoglycoside-permeant channels, and all of them are found expressed in the HCs [3537]. Exposure to immunostimulatory lipopolysaccharides, to simulate of bacterial infections, increased the cochlear expression of TRPV1 and hair cell uptake of gentamicin, thus, exacerbate ototoxicity of AGs [38]. In murine cochlear cultures, when the MET channels were disabled, the activated TRPA1 channels will facilitate the uptake of gentamicin [37].

2.2. Efforts in Inhibiting the Uptake of Drugs

Avoiding ototoxic drugs entry into HCs is the primary step. On the level of the MET channel, there are two possibilities exist. The first one is steric modification of the chemical structure of drugs. The MET channel pore, which has a diameter at its narrowest part of at least 1.25-1.5 nm, is large enough to allow AGs to enter the hair cell cytosol [39]. Therefore, widening the AG diameter by binding of certain molecules appears a promising strategy to inhibit AGs passing through the MET channel. But this biding must be irrelevant for antimicrobial activity [40]. The second way is blocking the MET channel to prevent ototoxic drugs entering HCs, especially for AGs. MET channel blocker, such as ORC-13661, can protect HCs against both AGs and cisplatin [41]. Because blocking of the MET channel would prevent hair cell depolarization and affect hearing function, therefore, the blockage must be temporary [42, 43].

Myosin7a is supposed to mediate AG endocytosis, and the uptake of AGs was decreased in Myosin7a mutant mice. This indicate a promising target for HC protection [44].

Intratympanic administration of copper sulfate, a CTR1 inhibitor, or knockdown of CTR1 with small interfering RNA can decrease the uptake and cytotoxicity of cisplatin and prevent hearing loss caused by cisplatin, both in vitro and in vivo [31]. OCT knockout or inhibition of OCT with cimetidine protects HCs against cisplatin-induced ototoxicity [34].

3. The Involvement of Mitochondrial Dysfunction and DNA Damage

The entry of AGs into HCs can lead to mtDNA mutations and thus affect the RNA translation and protein synthesis within mitochondria [45] and therefore leading to a decrease in ATP synthesis. With the decrease of energy production, the mitochondrial membrane integrity is compromised and thus leading to the leakage of cytochrome c, the generation of reactive oxygen species (ROS), and activation of stress kinases [46, 47]. The accumulation of ROS and cytochrome c will lead to the activation of the upstream caspases and subsequent apoptotic cell death. On the other hand, both ROS and stress kinases can cause cell death directly, as well as by amplifying insults targeting the mitochondria. And ROS can also cause mtDNA defects.

As for cisplatin, the ototoxic mechanism has been shown to be associated with several factors, such as oxidative stress, DNA damage, and inflammatory cytokines. Several studies have implicated the mitochondrial pathways in the apoptosis of HCs after cisplatin administration [48]. Exposure to cisplatin can also cause excessive generation of ROS via the NADPH-oxidase (NOX) pathway [49, 50], which will activate the mitochondrial apoptosis pathway that mentioned above. The signal transducers and activators of transcription 1 (STAT1) is an important mediator of cell death, and the STAT1 phosphorylation was found in HCs after exposure to cisplatin. STAT1 is involved in the response to the release of ROS, inflammatory cytokines, and DNA damage [51].

All these mechanisms of drug-induced hair cell death and protection will be discussed below.

3.1. Reactive Oxygen Species

ROS are mainly generated by the mitochondria in mammalian cells. AGs can combine with iron salts, and the iron-AG complexes catalyze free radical reactions and lead to ROS generation [52]. As mentioned above, AGs decrease the ATP synthesis, which will increase the permeability of mitochondrial transmembrane and the leakage of cyt-c and ROS. The ROS can also generate via the NOX3 pathway after cisplatin exposure. The ROS overload leads to the depletion of the cochlear antioxidant enzyme system (e.g., superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), which scavenges and neutralizes the generated superoxide and hydrogen peroxide [53]. The release of ROS causes further damage to mitochondrial components, such as mtDNA, mitochondrial membranes, and respiratory chain proteins, as well as nuclear DNA associated with mitochondrial function [54]. The ultimate effect of increased ROS generation is to promote apoptotic cell death, as described above.

3.2. Neutralization of Reactive Oxygen Species

Some studies have reported that antioxidants can promote HC survival in drug-induced ototoxicity, including coenzyme Q10 [55]; α-lipoic acid [56]; D-methionine [57]; thiourea [58]; vitamins B, C, and E [59]; N-acetylcysteine (NAC) [60]; and hormone melatonin [61]. Knockdown of NOX3 by intratympanic delivery of short interfering RNA (siRNA) protects against cisplatin-induced HC death [62]. Reducing the expression of TRPV1 or NOX3 can inhibit the ROS generation and the transcription factor STAT1 activation. And STAT1 activation will promote proapoptotic actions of cisplatin [63]. This indicates the inhibition of TRPV1 or NOX3 as promising approaches for reducing cisplatin ototoxicity. Another candidate strategy is the use of iron chelators, 2,3-dihydroxybenzoate [64], and acetylsalicylate (ASA) [65], which can compete with AGs for iron binding.

However, effects of these long-term treatments remain to be studied.

3.3. Caspase-Mediated Apoptosis

It has generally been accepted that the ototoxic drug-induced hair cell death shares a common pathway: caspase activation.

Caspases are divided into upstream and downstream members, which are normally inactive by binding with inhibitor of apoptosis proteins (IAP) [66, 67]. The upstream caspases are activated by proapoptotic signals, such as cytochrome c [68, 69], p53 [49], antiapoptotic Bcl-2 proteins [70, 71], tumor necrosis factor (TNF) family [72], and nuclear factor kappa B (NF-κB) [73]. And the downstream caspases are activated by upstream caspases.

Caspase-8 is an upstream member, which is linked to membrane-associated death receptors. Caspase-8 can activate by ligands such as Fas or TNF-α and subsequently activate downstream caspases such as caspases-3, -6, and -7 [72, 74]. Although caspase-8 is activated in HCs after AG administration [75], inhibition of this pathway does not prevent HC death or prevent caspase-3 activation [76]. Thus, it does not play a key role in HC death.

Caspase-9 is also an upstream member, which is triggered by nonreceptor stimulation, such as cytokine c releasing from mitochondrial [69]. After activation, caspase-9 can cleave and activate downstream caspases-3, which eventually leading to apoptotic HC death [75]. Caspase-3 is a downstream member, which mediates apoptotic program by cleaving proteins necessary for cell survival, such as cytoskeletal proteins [77]. The cisplatin-induced activation of caspase-9 and caspase-3 was seen in HEI/OC1 cells [78] and UB/OC1 cells [79].

3.4. Inhibition of Caspase Members

Studies have shown that intracochlear administration with specific inhibitors of caspase-9 or caspase-3 can prevent AG-induced or cisplatin-induced HC death and hearing loss [48, 80]. Caspase inhibitors, such as z-VAD-FMK and z-LEHD-FMK, can protect HCs against AG-induced cell death [81, 82]. Intracochlear perfusions with caspase-3 inhibitor (z-DEVD-fmk) and caspase-9 inhibitor (z-LEHD-fmk) prevent hearing loss and loss of HCs in cisplatin treated guinea pigs [48]. Several other efforts targeting the different steps in caspase activation are also promising. For example, NF-κB inhibitors, such as Bay 11-7085 or SN-50, can inhibit cisplatin-induced caspase-3 activation and apoptosis in HEI/OC1 cells [78].

3.5. BCL-2 Family

The Bcl-2 family can be categorized as antiapoptotic (e.g., Bcl-2 and Bcl-XL) or proapoptotic (e.g., Bax, Bak, Bcl-Xs, Bid, Bad, and Bim) members [83, 84]. Antiapoptotic Bcl-2 members can bind to proapoptotic Bcl-2 members, which will neutralize the proapoptotic signal [85]. The balance between the antiapoptotic and proapoptotic members is crucial for the living of the cell. When the balance tilts to proapoptosis, the proapoptotic Bcl-2 members, such as Bax and Bid, will translocate from the cytoplasm to the mitochondria, which will increase the permeability of mitochondrial transmembrane and lead to the generation of ROS and leakage of cytochrome c into the cytoplasm, thus eventually activate caspase-9 and caspase-3 and lead to apoptotic cell death as mentioned above [86, 87]. Recently, the increased expression of Bax and the decreased expression of Bcl-XL were observed in UB/OC-1 cells after cisplatin treatment [79]. The overexpression of Bcl-2 can inhibit the release of cytochrome c, thereby inhibiting the apoptosis cascade. This has been confirmed by some researchers in cochlear cell line or mouse utricles following AGs or cisplatin exposure [48, 70, 88].

3.6. Efforts on Targeting the Bcl-2 Family

Targeting the Bcl-2 family as the upstream mediator of apoptosis can prevent AG-induced hair cell death. Some studies reveal that overexpression of the antiapoptotic Bcl-2 members can inhibit apoptotic hair cell death following AG exposure in vitro and in vivo [70, 87, 89], while epigallocatechin gallate (EGCG), a known inhibitor of STAT1, can reverse the balance of Bax and Bcl-XL to antiapoptotic, which will protect HCs against apoptosis after cisplatin administration [79].

3.7. The c-jun NH2-Terminal Kinases (JNKs)

The c-jun NH2-terminal kinases (JNKs) are key modulators of apoptosis, which are activated in response to cellular insults, such as generation of ROS, in HCs treated with neomycin and cisplatin [90, 91]. JNK activation acts as upstream of cytochrome c redistribution and caspase activation [92, 93]. When activated, JNKs can activate the transcription factors c-Jun, c-FOS, ELK-1, and Bcl-2. After AG administration, the increased JNKs, c-Jun, c-FOS, and Bcl-2 have been observed in HCs [9496].

3.8. Inhibitors of the JNK Pathway

JNK inhibitors such as CEP-1347 [97] and CEP 11004 [91] can attenuate hair cell loss following AG administration. But, JNK inhibitor does not protect HCs against cisplatin-induced cell death, nor does it prevent redistribution of cytochrome c [48].

The mechanisms of AG-induced and cisplatin-induced HCs death are summarized in Figure 1.

3.9. Other Promising Targets

There are some other mechanisms underlying the ototoxic of AGs and cisplatin, such as heat shock proteins (HSP), p53, and NF-κβ as well as calcium-dependent proteases, and so on. Researchers have achieved promising outcomes. For example, overexpression of HSP-70 in transgenic mice can protect HCs against both aminoglycoside- and cisplatin-induced hair cell death [98, 99]. It is indicated that p53 acts upstream of mitochondrial apoptotic pathway and downregulation of the p53 gene protects HCs from cisplatin-induced Bax translocation, caspase-3 activation, cytochrome c translocation, and cell death [100]. Although p53 inhibitor protects against cisplatin-induced ototoxicity, the systemic application will interfere with the anticancer efficacy of cisplatin, while it is revealed that the intratympanic application of p53 inhibitor, such as pifithrin-a, protects auditory function without compromising the anticancer efficacy of cisplatin [100]. It has been revealed that Wnt/β-catenin signaling has an important role in protecting HCs against neomycin-induced HC loss. The overexpression of β-catenin can reduce forkhead box O3 transcription factor (Foxo3) and Bim expression and ROS levels after neomycin exposure [11]. This might be a new therapeutic target. Some researchers used rapamycin, an autophagy activator, to increase the autophagy activity and found that the ROS levels, apoptosis, and cell death were significantly decreased after neomycin or gentamicin exposure, suggesting that autophagy might be correlated with AG-induced HC death [101]. It is also revealed that meclofenamic acid can attenuate cisplatin-induced oxidative stress and apoptosis in HEI-OC1 cells, by inhibiting cisplatin-induced upregulation of autophagy [12].

3.10. Potential Drug Targets

With increased understanding of ototoxic cell death, a numerous of therapeutic efforts have been made to target different steps of in HC death. The HEI-OC1 and UB/OC-1 cell lines, organ explants, larval zebrafish lateral-line neuromasts, and some animal model (e.g., chicken, rat, mouse, and guinea pig) are the most commonly used research strategies. The delivery of test compounds can be performed by intratympanic, intraperitoneal, intramuscular, subcutaneous, intracochlear, and oral administration. Potential drug targets for treatment of AG and cisplatin ototoxicity are summarized in Table 1.


CompoundOtotoxic drugMechanismMaterials and methodsReferences

ORC-13661AG and cisplatinBlock MET channelMouse cochlear cultures, in vitro zebrafish, in vitro[41]
Copper sulfateCisplatinCTR1 inhibitor, inhibit uptakeHEI-OC1 cells, in vitro
Mice, in vivo, i.t.
[31]
CimetidineCisplatinOCT blocker, inhibit uptakeMice, in vivo, i.p.[34]
Coenzyme Q10CisplatinAntioxidantRat, in vivo, oral administrations[55]
α-Lipoic acidAGAntioxidantGuinea pigs, in vivo, i.m.[56]
D-MethionineAGAntioxidantGuinea pigs, in vivo, i.p.[57]
ThioureaCisplatinAntioxidantGuinea pigs, in vivo, intracochlear perfusion by osmotic pump[58]
Vitamins B, C, and ECisplatinAntioxidantRat, in vivo, i.p.[59]
N-AcetylcysteineAGAntioxidantRat, in vivo, i.p.[60]
Hormone melatoninCisplatinAntioxidantRat, in vivo, i.p.[61]
siRNACisplatinInhibit TRPV1 or NOX3
Inhibit ROS generation and STAT1 activation
UB/OC-1 cells, in vitro
Rat, in vivo, i.t.
[62]
2,3-DihydroxybenzoateAGIron chelators
Compete with AG for iron binding
Guinea pigs, in vivo, i.p.[64]
AcetylsalicylateAGIron chelators, compete with AG for iron binding
Antioxidant
Guinea pigs, in vivo, oral administration[65]
EGCGCisplatinSTAT1 inhibitor
Antiapoptotic
Rat, in vivo, oral administrations[79]
Bay 11-7085CisplatinNF-κB inhibitors
Inhibit caspase-3 activation
HEI/OC1 cells, in vivo[78]
SN-50CisplatinNF-κB inhibitors
Inhibit caspase-3 activation
HEI/OC1 cells, in vivo[78]
z-VAD-FMKAGGeneral caspase inhibitorGuinea pigs, in vivo, intracochlear perfusion by osmotic pump[81]
z-LEHD-FMKAGCaspase-9 inhibitorGuinea pigs, in vivo, intracochlear perfusion by osmotic pump[81]
z-DEVD-fmkCisplatinCaspase-3 inhibitorGuinea pigs, in vivo, intracochlear perfusion by minipump[48]
z-LEHD-fmkCisplatinCaspase-9 inhibitorGuinea pigs, in vivo, intracochlear perfusion by minipump[48]
CEP-1347AGJNK inhibitorGuinea pigs, in vivo, s.c.[97]
CEP 11004AGJNK inhibitorChicken vestibular hair cell culture, in vitro[91]
Pifithrin-aCisplatinp53 inhibitor
Inhibit mitochondrial apoptotic pathway
Mouse cochlear culture, in vitro[100]

AG: aminoglycoside; MET: mechanoelectrical transducer; CTR1: Copper Transporter 1; OCT: organic cation transporter; siRNA: short interfering RNA; TRP: transient receptor potential; NOX3: NADPH-oxidase 3; ROS: reactive oxygen species; STAT1: transcription factor; EGCG: epigallocatechin gallate; JNK: c-jun NH2-terminal kinase; i.t.: intratympanic; i.p.: intraperitoneal; i.m.: intramuscular; s.c.: subcutaneous.

4. Conclusion

As discussed above, many efforts have been made to protect HCs from cell death after ototoxic drug exposure. The outcomes are promising, but risks also arise. For example, endotoxemia-mediated inflammation can enhance aminoglycoside trafficking across the BLB and potentiate AG-induced ototoxicity. This indicates that patients with severe infections are at greater risk of AG-induced hearing loss than previously recognized. Systemic interference with cell signaling pathways may also have unknown physiological consequences. So, it is extremely different to apply clinically. For example, as an iron chelator, ASA itself is ototoxic and can cause tinnitus, vertigo, and hearing loss. On the other side, long-term treatment with antiapoptotic drugs bears a potential carcinogenic risk, as apoptosis is crucial in preventing uncontrolled cell proliferation. Although antioxidants are well established as otoprotectants, some studies show that administered of a single antioxidant in high oxidative environment would be rapidly oxidized and produce only transient benefit in preventing hearing loss [102]. As for AGs can remain in HCs for months, thus, use of a single antioxidant in high-risk human populations has not produced expected benefits; the outcomes of long-term and mixture administration with other drugs are also need to be well studied.

A variety kind of insults to the inner ear can cause HC death and hearing loss. Although the most predominant form of drug-induced cell death is apoptosis, necrotic features are also seen in HCs following AG exposure [19]. This suggests that the apoptotic and necrotic cell death that occurs in HCs may share among many ototoxic events, while the necrosis and associated pathways are still unclear in HCs after ototoxic drug exposure. Research in the mechanisms of regulated necrosis in HCs may improve our understanding of the complex communications between different signaling cascades. On the other side, great progresses have been made in the field of HC regeneration. For example, it has been reported that Lgr5-expressing cells can differentiate into HCs [17], and several genes have been identified that regulate the regeneration of HCs [13, 18]. These are also promising strategies.

Thus, a full understanding of the mechanisms in ototoxic drug-induced hearing loss still remains urgent, and the possibility of future clinical utilization is also need to be well evaluated.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Acknowledgments

This research was jointly supported by the Zhejiang Provincial Natural Science Foundation of China and the Wenzhou basic scientific research project under Grant Nos. LY19H130003, LY19H130004, Y20H130015, and Y20180091.

References

  1. J. Guo, R. Chai, H. Li, and S. Sun, “Protection of hair cells from ototoxic drug-induced hearing loss,” Advances in Experimental Medicine and Biology, vol. 1130, pp. 17–36, 2019. View at: Publisher Site | Google Scholar
  2. Y. Liu, J. Qi, X. Chen et al., “Critical role of spectrin in hearing development and deafness,” Science advances, vol. 5, no. 4, article eaav7803, 2019. View at: Publisher Site | Google Scholar
  3. Y. Wang, J. Li, X. Yao et al., “Loss of CIB2 causes profound hearing loss and abolishes mechanoelectrical transduction in mice,” Frontiers in Molecular Neuroscience, vol. 10, p. 401, 2017. View at: Publisher Site | Google Scholar
  4. C. Zhu, C. Cheng, Y. Wang et al., “Loss of ARHGEF6 causes hair cell stereocilia deficits and hearing loss in mice,” Frontiers in Molecular Neuroscience, vol. 11, p. 362, 2018. View at: Publisher Site | Google Scholar
  5. J. Qi, Y. Liu, C. Chu et al., “A cytoskeleton structure revealed by super-resolution fluorescence imaging in inner ear hair cells,” Cell Discovery, vol. 5, no. 1, p. 12, 2019. View at: Publisher Site | Google Scholar
  6. J. Qi, L. Zhang, F. Tan et al., “Espin distribution as revealed by super-resolution microscopy of stereocilia,” American Journal of Translational Research, vol. 12, no. 1, pp. 130–141, 2020. View at: Google Scholar
  7. Z. H. He, S. Y. Zou, M. Li et al., “The nuclear transcription factor FoxG1 affects the sensitivity of mimetic aging hair cells to inflammation by regulating autophagy pathways,” Redox Biology, vol. 28, article 101364, 2020. View at: Publisher Site | Google Scholar
  8. S. Gao, C. Cheng, M. Wang et al., “Blebbistatin inhibits neomycin-induced apoptosis in hair cell-like HEI-OC-1 cells and in cochlear hair cells,” Frontiers in Cellular Neuroscience, vol. 13, p. 590, 2019. View at: Publisher Site | Google Scholar
  9. Y. Zhang, W. Li, Z. He et al., “Pre-treatment with fasudil prevents neomycin-induced hair cell damage by reducing the accumulation of reactive oxygen species,” Frontiers in Molecular Neuroscience, vol. 12, p. 264, 2019. View at: Publisher Site | Google Scholar
  10. W. Liu, X. Xu, Z. Fan et al., “Wnt signaling activates TP53-induced glycolysis and apoptosis regulator and protects against cisplatin-induced spiral ganglion neuron damage in the mouse cochlea,” Antioxidants & Redox Signaling, vol. 30, no. 11, pp. 1389–1410, 2019. View at: Publisher Site | Google Scholar
  11. L. Liu, Y. Chen, J. Qi et al., “Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea,” Cell Death & Disease, vol. 7, no. 3, article e2136, 2016. View at: Publisher Site | Google Scholar
  12. H. Li, Y. Song, Z. He et al., “Meclofenamic acid reduces reactive oxygen species accumulation and apoptosis, inhibits excessive autophagy, and protects hair cell-like HEI-OC1 cells from cisplatin-induced damage,” Frontiers in Cellular Neuroscience, vol. 12, p. 139, 2018. View at: Publisher Site | Google Scholar
  13. S. Zhang, Y. Zhang, Y. Dong et al., “Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea,” Cellular and Molecular Life Sciences, vol. 77, no. 7, pp. 1401–1419, 2020. View at: Publisher Site | Google Scholar
  14. F. Tan, C. Chu, J. Qi et al., “AAV-ie enables safe and efficient gene transfer to inner ear cells,” Nature Communications, vol. 10, no. 1, p. 3733, 2019. View at: Publisher Site | Google Scholar
  15. C. Cheng, Y. Wang, L. Guo et al., “Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea,” Stem Cell Research & Therapy, vol. 10, no. 1, p. 365, 2019. View at: Publisher Site | Google Scholar
  16. X. Lu, S. Sun, J. Qi et al., “Bmi1 regulates the proliferation of cochlear supporting cells via the canonical Wnt signaling pathway,” Molecular Neurobiology, vol. 54, no. 2, pp. 1326–1339, 2017. View at: Publisher Site | Google Scholar
  17. T. Wang, R. Chai, G. S. Kim et al., “Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle,” Nature Communications, vol. 6, no. 1, p. 6613, 2015. View at: Publisher Site | Google Scholar
  18. B. C. Cox, R. Chai, A. Lenoir et al., “Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo,” Development, vol. 141, no. 4, pp. 816–829, 2014. View at: Publisher Site | Google Scholar
  19. C. T. Dinh, S. Goncalves, E. Bas, T. R. Van De Water, and A. Zine, “Molecular regulation of auditory hair cell death and approaches to protect sensory receptor cells and/or stimulate repair following acoustic trauma,” Frontiers in Cellular Neuroscience, vol. 9, p. 96, 2015. View at: Publisher Site | Google Scholar
  20. A. Li, D. You, W. Li et al., “Novel compounds protect auditory hair cells against gentamycin-induced apoptosis by maintaining the expression level of H3K4me2,” Drug Delivery, vol. 25, no. 1, pp. 1033–1043, 2018. View at: Publisher Site | Google Scholar
  21. S. Sun, M. Sun, Y. Zhang et al., “In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period,” Frontiers in Cellular Neuroscience, vol. 8, p. 248, 2014. View at: Publisher Site | Google Scholar
  22. Z. He, S. Sun, M. Waqas et al., “Reduced TRMU expression increases the sensitivity of hair-cell-like HEI-OC-1 cells to neomycin damage in vitro,” Scientific Reports, vol. 6, no. 1, article 29621, 2016. View at: Publisher Site | Google Scholar
  23. X. Yu, W. Liu, Z. Fan et al., “c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI- OC1 cells in vitro,” Scientific Reports, vol. 7, article 41094, no. 1, 2017. View at: Publisher Site | Google Scholar
  24. Q. Wang and P. S. Steyger, “Trafficking of systemic fluorescent gentamicin into the cochlea and hair cells,” Journal of the Association for Research in Otolaryngology, vol. 10, no. 2, pp. 205–219, 2009. View at: Publisher Site | Google Scholar
  25. A. Alharazneh, L. Luk, M. Huth et al., “Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity,” PLoS One, vol. 6, no. 7, article e22347, 2011. View at: Publisher Site | Google Scholar
  26. A. A. Vu, G. S. Nadaraja, M. E. Huth et al., “Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death,” PLoS One, vol. 8, no. 1, article e54794, 2013. View at: Publisher Site | Google Scholar
  27. E. Hashino and M. Shero, “Endocytosis of aminoglycoside antibiotics in sensory hair cells,” Brain Research, vol. 704, no. 1, pp. 135–140, 1995. View at: Publisher Site | Google Scholar
  28. B. Nilius and A. Szallasi, “Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine,” Pharmacological Reviews, vol. 66, no. 3, pp. 676–814, 2014. View at: Publisher Site | Google Scholar
  29. W. Marcotti, S. M. van Netten, and C. J. Kros, “The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels,” The Journal of Physiology, vol. 567, no. 2, pp. 505–521, 2005. View at: Publisher Site | Google Scholar
  30. J. E. Gale, W. Marcotti, H. J. Kennedy, C. J. Kros, and G. P. Richardson, “FM1-43 dye behaves as a permeant blocker of the hair-cell mechanotransducer channel,” The Journal of Neuroscience, vol. 21, no. 18, pp. 7013–7025, 2001. View at: Publisher Site | Google Scholar
  31. S. S. More, O. Akil, A. G. Ianculescu, E. G. Geier, L. R. Lustig, and K. M. Giacomini, “Role of the copper transporter, CTR1, in platinum-induced ototoxicity,” The Journal of Neuroscience, vol. 30, no. 28, pp. 9500–9509, 2010. View at: Publisher Site | Google Scholar
  32. A. J. Thomas, D. W. Hailey, T. M. Stawicki et al., “Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line,” The Journal of Neuroscience, vol. 33, no. 10, pp. 4405–4414, 2013. View at: Publisher Site | Google Scholar
  33. S. Sheth, D. Mukherjea, L. P. Rybak, and V. Ramkumar, “Mechanisms of cisplatin-induced ototoxicity and otoprotection,” Frontiers in Cellular Neuroscience, vol. 11, p. 338, 2017. View at: Publisher Site | Google Scholar
  34. G. Ciarimboli, D. Deuster, A. Knief et al., “Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions,” The American Journal of Pathology, vol. 176, no. 3, pp. 1169–1180, 2010. View at: Publisher Site | Google Scholar
  35. J. Zheng, C. Dai, P. S. Steyger et al., “Vanilloid receptors in hearing: altered cochlear sensitivity by vanilloids and expression of TRPV1 in the organ of corti,” Journal of Neurophysiology, vol. 90, no. 1, pp. 444–455, 2003. View at: Publisher Site | Google Scholar
  36. S. E. Myrdal and P. S. Steyger, “TRPV1 regulators mediate gentamicin penetration of cultured kidney cells,” Hearing Research, vol. 204, no. 1-2, pp. 170–182, 2005. View at: Publisher Site | Google Scholar
  37. R. S. Stepanyan, A. A. Indzhykulian, A. C. Vélez-Ortega et al., “TRPA1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells,” Journal of the Association for Research in Otolaryngology, vol. 12, no. 6, pp. 729–740, 2011. View at: Publisher Site | Google Scholar
  38. M. Jiang, H. Li, A. Johnson et al., “Inflammation up-regulates cochlear expression of TRPV1 to potentiate drug-induced hearing loss,” Science advances, vol. 5, no. 7, article eaaw1836, 2019. View at: Publisher Site | Google Scholar
  39. H. E. Farris, C. L. LeBlanc, J. Goswami, and A. J. Ricci, “Probing the pore of the auditory hair cell mechanotransducer channel in turtle,” The Journal of Physiology, vol. 558, no. 3, pp. 769–792, 2004. View at: Publisher Site | Google Scholar
  40. M. E. Huth, A. J. Ricci, and A. G. Cheng, “Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection,” International journal of otolaryngology, vol. 2011, Article ID 937861, 19 pages, 2011. View at: Publisher Site | Google Scholar
  41. S. R. Kitcher, N. K. Kirkwood, E. D. Camci et al., “ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity,” JCI Insight, vol. 4, no. 15, 2019. View at: Publisher Site | Google Scholar
  42. A. Ricci, “Differences in mechano-transducer channel kinetics underlie tonotopic distribution of fast adaptation in auditory hair cells,” Journal of Neurophysiology, vol. 87, no. 4, pp. 1738–1748, 2002. View at: Publisher Site | Google Scholar
  43. A. J. Hudspeth, Y. Choe, A. D. Mehta, and P. Martin, “Putting ion channels to work: mechanoelectrical transduction, adaptation, and amplification by hair cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 22, pp. 11765–11772, 2000. View at: Publisher Site | Google Scholar
  44. T. Hasson, P. G. Gillespie, J. A. Garcia et al., “Unconventional myosins in inner-ear sensory epithelia,” The Journal of Cell Biology, vol. 137, no. 6, pp. 1287–1307, 1997. View at: Publisher Site | Google Scholar
  45. S. N. Hobbie, S. Akshay, S. K. Kalapala, C. M. Bruell, D. Shcherbakov, and E. C. Böttger, “Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20888–20893, 2008. View at: Publisher Site | Google Scholar
  46. H. Li, A. Kachelmeier, D. N. Furness, and P. S. Steyger, “Local mechanisms for loud sound-enhanced aminoglycoside entry into outer hair cells,” Frontiers in Cellular Neuroscience, vol. 9, p. 130, 2015. View at: Publisher Site | Google Scholar
  47. M. X. Guan, “Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity,” Mitochondrion, vol. 11, no. 2, pp. 237–245, 2011. View at: Publisher Site | Google Scholar
  48. J. Wang, S. Ladrech, R. Pujol, P. Brabet, T. R. Van De Water, and J. L. Puel, “Caspase inhibitors, but not c-Jun NH2-terminal kinase inhibitor treatment, prevent cisplatin-induced hearing loss,” Cancer Research, vol. 64, no. 24, pp. 9217–9224, 2004. View at: Publisher Site | Google Scholar
  49. J. R. García-Berrocal, J. Nevado, R. Ramírez-Camacho et al., “The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear,” British Journal of Pharmacology, vol. 152, no. 7, pp. 1012–1020, 2007. View at: Publisher Site | Google Scholar
  50. C. Casares, R. Ramírez-Camacho, A. Trinidad, A. Roldán, E. Jorge, and J. R. García-Berrocal, “Reactive oxygen species in apoptosis induced by cisplatin: review of physiopathological mechanisms in animal models,” European Archives of Oto-Rhino-Laryngology, vol. 269, no. 12, pp. 2455–2459, 2012. View at: Publisher Site | Google Scholar
  51. N. C. Schmitt, E. W. Rubel, and N. M. Nathanson, “Cisplatin-induced hair cell death requires STAT1 and is attenuated by epigallocatechin gallate,” The Journal of Neuroscience, vol. 29, no. 12, pp. 3843–3851, 2009. View at: Publisher Site | Google Scholar
  52. S. Denamur, D. Tyteca, J. Marchand-Brynaert et al., “Role of oxidative stress in lysosomal membrane permeabilization and apoptosis induced by gentamicin, an aminoglycoside antibiotic,” Free Radical Biology & Medicine, vol. 51, no. 9, pp. 1656–1665, 2011. View at: Publisher Site | Google Scholar
  53. D. Mukherjea, S. Ghosh, P. Bhatta et al., “Early investigational drugs for hearing loss,” Expert Opinion on Investigational Drugs, vol. 24, no. 2, pp. 201–217, 2015. View at: Publisher Site | Google Scholar
  54. N. D. Bonawitz, M. S. Rodeheffer, and G. S. Shadel, “Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span,” Molecular and Cellular Biology, vol. 26, no. 13, pp. 4818–4829, 2006. View at: Publisher Site | Google Scholar
  55. L. Astolfi, E. Simoni, F. Valente et al., “Correction: coenzyme Q10 plus multivitamin treatment prevents cisplatin ototoxicity in rats,” PLoS One, vol. 12, no. 9, article e0185525, 2017. View at: Publisher Site | Google Scholar
  56. B. J. Conlon, J. M. Aran, J. P. Erre, and D. W. Smith, “Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid,” Hearing Research, vol. 128, no. 1-2, pp. 40–44, 1999. View at: Publisher Site | Google Scholar
  57. D. J. Fox, M. D. Cooper, C. A. Speil et al., “d-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models,” Journal of Cystic Fibrosis, vol. 15, no. 4, pp. 518–530, 2016. View at: Publisher Site | Google Scholar
  58. A. Ekborn, G. Laurell, H. Ehrsson, and J. Miller, “Intracochlear administration of thiourea protects against cisplatin-induced outer hair cell loss in the guinea pig,” Hearing Research, vol. 181, no. 1-2, pp. 109–115, 2003. View at: Publisher Site | Google Scholar
  59. S. A. Tokgöz, E. Vuralkan, N. D. Sonbay et al., “Protective effects of vitamins E, B and C and L-carnitine in the prevention of cisplatin-induced ototoxicity in rats,” The Journal of Laryngology and Otology, vol. 126, no. 5, pp. 464–469, 2012. View at: Publisher Site | Google Scholar
  60. I. Aladag, M. Guven, and M. Songu, “Prevention of gentamicin ototoxicity with N-acetylcysteine and vitamin A,” The Journal of Laryngology and Otology, vol. 130, no. 5, pp. 440–446, 2016. View at: Publisher Site | Google Scholar
  61. J. de Araujo, L. S. M. Serra, L. Lauand, S. A. S. Kückelhaus, and A. L. L. Sampaio, “Protective effect of melatonin on cisplatin-induced ototoxicity in rats,” Anticancer Research, vol. 39, no. 5, pp. 2453–2458, 2019. View at: Publisher Site | Google Scholar
  62. D. Mukherjea, S. Jajoo, C. Whitworth et al., “Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat,” The Journal of Neuroscience, vol. 28, no. 49, pp. 13056–13065, 2008. View at: Publisher Site | Google Scholar
  63. T. Kaur, D. Mukherjea, K. Sheehan, S. Jajoo, L. P. Rybak, and V. Ramkumar, “Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation,” Cell Death & Disease, vol. 2, no. 7, article e180, 2011. View at: Publisher Site | Google Scholar
  64. P. Sinswat, W. J. Wu, S. H. Sha, and J. Schacht, “Protection from ototoxicity of intraperitoneal gentamicin in guinea pig,” Kidney International, vol. 58, no. 6, pp. 2525–2532, 2000. View at: Publisher Site | Google Scholar
  65. S. H. Sha and J. Schacht, “Salicylate attenuates gentamicin-induced ototoxicity,” Laboratory Investigation, vol. 79, no. 7, pp. 807–813, 1999. View at: Google Scholar
  66. A. G. Cheng, L. L. Cunningham, and E. W. Rubel, “Mechanisms of hair cell death and protection,” Current Opinion in Otolaryngology & Head and Neck Surgery, vol. 13, no. 6, pp. 343–348, 2005. View at: Publisher Site | Google Scholar
  67. D. Brenner and T. W. Mak, “Mitochondrial cell death effectors,” Current Opinion in Cell Biology, vol. 21, no. 6, pp. 871–877, 2009. View at: Publisher Site | Google Scholar
  68. L. M. Leoni, Q. Chao, H. B. Cottam et al., “Induction of an apoptotic program in cell-free extracts by 2-chloro-2'-deoxyadenosine 5'-triphosphate and cytochrome c,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 16, pp. 9567–9571, 1998. View at: Publisher Site | Google Scholar
  69. H. R. Stennicke and G. S. Salvesen, “Caspases - controlling intracellular signals by protease zymogen activation,” Biochimica et Biophysica Acta, vol. 1477, no. 1-2, pp. 299–306, 2000. View at: Publisher Site | Google Scholar
  70. L. L. Cunningham, J. I. Matsui, M. E. Warchol, and E. W. Rubel, “Overexpression of Bcl-2 prevents neomycin-induced hair cell death and caspase-9 activation in the adult mouse utricle in vitro,” Journal of Neurobiology, vol. 60, no. 1, pp. 89–100, 2004. View at: Publisher Site | Google Scholar
  71. A. B. Coffin, E. W. Rubel, and D. W. Raible, “Bax, Bcl2, and p53 differentially regulate neomycin- and gentamicin-induced hair cell death in the zebrafish lateral line,” Journal of the Association for Research in Otolaryngology, vol. 14, no. 5, pp. 645–659, 2013. View at: Publisher Site | Google Scholar
  72. M. Muzio, B. R. Stockwell, H. R. Stennicke, G. S. Salvesen, and V. M. Dixit, “An induced proximity model for caspase-8 activation,” The Journal of Biological Chemistry, vol. 273, no. 5, pp. 2926–2930, 1998. View at: Publisher Site | Google Scholar
  73. H. So, H. Kim, Y. Kim et al., “Evidence that cisplatin-induced auditory damage is attenuated by downregulation of pro-inflammatory cytokines via Nrf2/HO-1,” Journal of the Association for Research in Otolaryngology, vol. 9, no. 3, pp. 290–306, 2008. View at: Publisher Site | Google Scholar
  74. M. E. Peter and P. H. Krammer, “The CD95(APO-1/Fas) DISC and beyond,” Cell Death and Differentiation, vol. 10, no. 1, pp. 26–35, 2003. View at: Publisher Site | Google Scholar
  75. L. L. Cunningham, A. G. Cheng, and E. W. Rubel, “Caspase activation in hair cells of the mouse utricle exposed to neomycin,” The Journal of Neuroscience, vol. 22, no. 19, pp. 8532–8540, 2002. View at: Publisher Site | Google Scholar
  76. D. Bodmer, D. Brors, K. Pak, M. Bodmer, and A. F. Ryan, “Gentamicin-induced hair cell death is not dependent on the apoptosis receptor Fas,” The Laryngoscope, vol. 113, no. 3, pp. 452–455, 2003. View at: Publisher Site | Google Scholar
  77. S. Kothakota, T. Azuma, C. Reinhard et al., “Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis,” Science, vol. 278, no. 5336, pp. 294–298, 1997. View at: Publisher Site | Google Scholar
  78. W. H. Chung, S. H. Boo, M. K. Chung, H. S. Lee, Y. S. Cho, and S. H. Hong, “Proapoptotic effects of NF-kappaB on cisplatin-induced cell death in auditory cell line,” Acta Oto-Laryngologica, vol. 128, no. 10, pp. 1063–1070, 2008. View at: Publisher Site | Google Scholar
  79. V. Borse, R. F. H. al Aameri, K. Sheehan et al., “Epigallocatechin-3-gallate, a prototypic chemopreventative agent for protection against cisplatin-based ototoxicity,” Cell Death & Disease, vol. 8, no. 7, article e2921, 2017. View at: Publisher Site | Google Scholar
  80. W. Liu, H. Staecker, H. Stupak, B. Malgrange, P. Lefebvre, and T. R. Van De Water, “Caspase inhibitors prevent cisplatin-induced apoptosis of auditory sensory cells,” Neuroreport, vol. 9, no. 11, pp. 2609–2614, 1998. View at: Publisher Site | Google Scholar
  81. T. Okuda, K. Sugahara, T. Takemoto, H. Shimogori, and H. Yamashita, “Inhibition of caspases alleviates gentamicin-induced cochlear damage in guinea pigs,” Auris, Nasus, Larynx, vol. 32, no. 1, pp. 33–37, 2005. View at: Publisher Site | Google Scholar
  82. J. I. Matsui, A. Haque, D. Huss et al., “Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo,” The Journal of Neuroscience, vol. 23, no. 14, pp. 6111–6122, 2003. View at: Publisher Site | Google Scholar
  83. C. Borner, “The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions,” Molecular Immunology, vol. 39, no. 11, pp. 615–647, 2003. View at: Publisher Site | Google Scholar
  84. T. Lindsten, W. X. Zong, and C. B. Thompson, “Defining the role of the Bcl-2 family of proteins in the nervous system,” The Neuroscientist, vol. 11, no. 1, pp. 10–15, 2005. View at: Publisher Site | Google Scholar
  85. H. Xiang, Y. Kinoshita, C. M. Knudson, S. J. Korsmeyer, P. A. Schwartzkroin, and R. S. Morrison, “Bax involvement in p53-mediated neuronal cell death,” The Journal of Neuroscience, vol. 18, no. 4, pp. 1363–1373, 1998. View at: Publisher Site | Google Scholar
  86. S. Shimizu, Y. Eguchi, W. Kamiike et al., “Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 4, pp. 1455–1459, 1998. View at: Publisher Site | Google Scholar
  87. S. C. Pfannenstiel, M. Praetorius, P. K. Plinkert, D. E. Brough, and H. Staecker, “Bcl-2 gene therapy prevents aminoglycoside-induced degeneration of auditory and vestibular hair cells,” Audiology & Neuro-Otology, vol. 14, no. 4, pp. 254–266, 2009. View at: Publisher Site | Google Scholar
  88. P. Devarajan, M. Savoca, M. P. Castaneda et al., “Cisplatin-induced apoptosis in auditory cells: role of death receptor and mitochondrial pathways,” Hearing Research, vol. 174, no. 1-2, pp. 45–54, 2002. View at: Publisher Site | Google Scholar
  89. Y. H. Liu, X. M. Ke, Y. Qin, Z. P. Gu, and S. F. Xiao, “Adeno-associated virus-mediated Bcl-xL prevents aminoglycoside-induced hearing loss in mice,” Chinese Medical Journal, vol. 120, no. 14, pp. 1236–1240, 2007. View at: Publisher Site | Google Scholar
  90. H. M. Shen and Z. G. Liu, “JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species,” Free Radical Biology & Medicine, vol. 40, no. 6, pp. 928–939, 2006. View at: Publisher Site | Google Scholar
  91. J. I. Matsui, J. E. Gale, and M. E. Warchol, “Critical signaling events during the aminoglycoside-induced death of sensory hair cells in vitro,” Journal of Neurobiology, vol. 61, no. 2, pp. 250–266, 2004. View at: Publisher Site | Google Scholar
  92. K. Sugahara, E. W. Rubel, and L. L. Cunningham, “JNK signaling in neomycin-induced vestibular hair cell death,” Hearing Research, vol. 221, no. 1-2, pp. 128–135, 2006. View at: Publisher Site | Google Scholar
  93. J. E. Lee, T. Nakagawa, T. S. Kim et al., “Signaling pathway for apoptosis of vestibular hair cells of mice due to aminoglycosides,” Acta Oto-Laryngologica. Supplementum, vol. 124, pp. 69–74, 2004. View at: Publisher Site | Google Scholar
  94. L. P. Rybak and C. A. Whitworth, “Ototoxicity: therapeutic opportunities,” Drug Discovery Today, vol. 10, no. 19, pp. 1313–1321, 2005. View at: Publisher Site | Google Scholar
  95. U. Pirvola, L. Xing-Qun, J. Virkkala et al., “Rescue of hearing, auditory hair cells, and neurons by CEP-1347/KT7515, an inhibitor of c-Jun N-terminal kinase activation,” The Journal of Neuroscience, vol. 20, no. 1, pp. 43–50, 2000. View at: Publisher Site | Google Scholar
  96. J. Wang, T. R. Van De Water, C. Bonny, F. de Ribaupierre, J. L. Puel, and A. Zine, “A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss,” The Journal of Neuroscience, vol. 23, no. 24, pp. 8596–8607, 2003. View at: Publisher Site | Google Scholar
  97. A. A. Eshraghi, J. Wang, E. Adil et al., “Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity,” Hearing Research, vol. 226, no. 1-2, pp. 168–177, 2007. View at: Publisher Site | Google Scholar
  98. T. G. Baker, S. Roy, C. S. Brandon et al., “Heat shock protein-mediated protection against cisplatin-induced hair cell death,” Journal of the Association for Research in Otolaryngology, vol. 16, no. 1, pp. 67–80, 2015. View at: Publisher Site | Google Scholar
  99. M. Taleb, C. S. Brandon, F. S. Lee, K. C. Harris, W. H. Dillmann, and L. L. Cunningham, “Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death,” Cell Stress & Chaperones, vol. 14, no. 4, pp. 427–437, 2009. View at: Publisher Site | Google Scholar
  100. N. Benkafadar, J. Menardo, J. Bourien et al., “Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy,” EMBO Molecular Medicine, vol. 9, no. 1, pp. 7–26, 2017. View at: Publisher Site | Google Scholar
  101. Z. He, L. Guo, Y. Shu et al., “Autophagy protects auditory hair cells against neomycin-induced damage,” Autophagy, vol. 13, no. 11, pp. 1884–1904, 2017. View at: Publisher Site | Google Scholar
  102. K. N. Prasad and S. C. Bondy, “Increased oxidative stress, inflammation, and glutamate: potential preventive and therapeutic targets for hearing disorders,” Mechanisms of Ageing and Development, vol. 185, article 111191, 2020. View at: Publisher Site | Google Scholar

Copyright © 2021 Peng Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views179
Downloads190
Citations

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.