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Review

Role of Oxidative Stress in Sensorineural Hearing Loss

by
Masato Teraoka
1,*,
Naohito Hato
1,
Haruhiko Inufusa
2 and
Fukka You
2
1
Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Ehime University, Toon 791-0295, Ehime, Japan
2
Division of Anti-Oxidant Research, Life Science Research Center, Gifu University, Yanagito 1-1, Gifu 501-1194, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(8), 4146; https://doi.org/10.3390/ijms25084146
Submission received: 20 February 2024 / Revised: 27 March 2024 / Accepted: 8 April 2024 / Published: 9 April 2024
(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

Abstract

:
Hearing is essential for communication, and its loss can cause a serious disruption to one’s social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia–reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described.

1. Introduction

Hearing, which is integral to communication, is a sensory ability shared by most animals, and its loss significantly impairs social life. There are various causes of hearing loss, including congenital hearing loss, which is mainly due to genetic predisposition, age-related hearing loss (ARHL, which will be restricted to sensorineural hearing loss in the context of this review), noise-induced hearing loss (NIHL), and hearing loss caused by drugs and other chemicals, or by ischemia [1]. Hearing loss is not only a physical and financial burden on one’s social life but also contributes to psychological problems and psychiatric disorders, including cognitive decline and depression [2,3]. The growing recognition of hearing loss as a major risk factor for dementia underscores the urgency of addressing it as a global issue [4,5,6,7]. The World Health Organization (WHO) estimates that by 2050, a staggering 2.5 billion people, primarily those over 60 years old, will be living with some degree of hearing loss [8,9,10].
Hearing loss can be caused by various factors; however, damage to hair cells in the cochlea of the inner ear is irreversible. Aging is the most common cause of hearing loss due to this inner ear damage, and its underlying mechanisms are becoming increasingly clear. In 1956, Harman proposed the free radical theory, which states that the production of reactive oxygen species (ROS) and their subsequent damage to biological components are key factors in the aging process [11]. Free radicals are defined as molecular entities or molecular fragments containing one or more unpaired electrons. ROS include both free-radical and non-radical derivatives of oxygen [12]. Because mitochondria are a major source of intracellular ROS, the link between aging and ROS has been the focus of mitochondrial research [13]. ROS production is implicated in several apoptotic and necrotic cell death pathways in the auditory structures [14] and can cause most types of sensorineural hearing loss (SNHL), including ARHL, hereditary hearing loss, ototoxic drug-induced hearing loss (DIHL), and NIHL. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies, including noise-induced, ototoxic drug-induced, and age-related cochlear degeneration. Oxidative stress and ROS disruption of the redox state have been implicated in cochlear damage [15,16,17]. The cochlea is one of the most susceptible organs to oxidative stress, owing to the high metabolic demands of hair cells in response to sound stimuli. These findings, together with the elucidation of various mechanisms related to hearing loss and ROS, have led to intensive research on the use of antioxidants in the treatment of inner ear disorders. Notably, animal studies are beginning to demonstrate their efficacy; however, the role of antioxidants in human studies remains controversial, with many uncertain results. This review outlines the auditory system and SNHL, mainly due to inner-ear damage, focusing on the relationship between hearing loss and ROS, particularly in ARHL, NIHL, DIHL, and ischemia–reperfusion injury. Based on these mechanisms, we discuss the current status and future perspectives of ROS-targeted therapies for SNHL.

2. Auditory System and Sensorineural Hearing Loss

Sound is the result of air vibrations, and the brain has a highly successful mechanism for detecting it [18]. Air vibrations travel to the outer ear and are transmitted to the tympanic membrane and through the middle ear. Connected by three ossicles to the inner ear, the middle ear amplifies the vibrations and transmits them to the inner ear. The cochlea, a part of the inner ear, contains a spiral row of sensory cells called hair cells. Cochlear function is essential for sound recognition in the brain. In humans, the cochlea is a bony organ that forms a two-and-a-half-turn spiral with the cochlear axis at the center. The basilar membrane and organ of Corti exist between the scala tympani and the cochlear duct, whereas the cochlear duct and scala vestibuli are separated by Reissner’s membrane. The scala tympani and vestibuli are connected by a helicotrema at the apical turn. This area contains perilymph fluid, which is similar in composition to normal extracellular fluid. In contrast, the cochlear duct is filled with endolymphatic fluid rich in K+ [19]. The organ of Corti has a single row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs) [20,21]. In humans, there are about 16,000 hair cells, both inner and outer, in the cochlea [22]. These cells have stereocilia, the lower end of which connects to a protein complex containing an ion channel called the mechanoelectric transducer channel. IHCs are mainly innervated by auditory afferent fibers, whereas OHCs are mainly innervated by inhibitory efferent fibers. When sound enters the ear, the footplate of the stapes vibrates, transmitting the vibrations to the basilar membrane [23]. These vibrations cause the IHCs to depolarize, leading to the release of neurotransmitters and the generation of action potentials [24]. OHCs are motile, contracting upon depolarization and expanding upon hyperpolarization [25]. The vibrations of the basilar membrane, enhanced by the OHCs, amplify this electro-mechanical conversion. These electrical signals are transmitted to the brain via the nerves and are ultimately recognized as sound [18].
Hearing loss occurs when any part of the auditory system is affected. There are two types of hearing loss: conductive hearing loss and SNHL. Although SNHL is the most common type of hearing loss, it is usually not treatable by medical or surgical means once the symptoms have passed without improvement. SNHL arises from a dysfunction in the cochlear or nerve pathways involved in hearing. Genetic mutations are critical causal factors of SNHL; several pathologies have also been implicated, including ischemia, infection, intense noise [26,27,28], trauma, aging, the use of ototoxic drugs [29,30], and autoimmunity. Despite the diverse adverse factors, many common factors, such as the influence of ROS and inflammatory cytokines, are believed to be pivotal in causing hearing loss, mainly by damaging hair cells. Treatment with corticosteroids aims to prevent the progression of the damage [31]. Steroids exhibit various physiological activities, including anti-inflammatory and immunosuppressive effects. However, many patients with SNHL do not recover adequately despite optimal treatment [16], warranting the need for an enhanced understanding of the pathophysiology and the development of new treatments [32].

3. Reactive Oxygen Species

ROS comprise highly reactive oxygen molecules involved in oxidation reactions, with the most common examples being superoxide (O2), hydrogen peroxide (H2O2), hydroxyl radicals (•OH), and singlet oxygen. The broader term also includes nitric oxide (NO), nitrogen dioxide, and ozone. Although once considered solely toxic to organisms, ROS have been reported to play important beneficial roles as well. When the equilibrium between the production and elimination of ROS is disrupted, affecting cell physiology, this state is termed oxidative stress [33]. Low ROS levels are required for cell proliferation, differentiation, and survival, whereas moderately increased ROS levels can cause DNA damage and promote mutations [34,35,36]. High ROS levels ultimately cause oxidative stress and lead to cellular damage and death. ROS are chemically reactive species containing unpaired electrons and are highly toxic to cells and intracellular structures. It is estimated that ROS are associated with more than 100 clinical symptoms [37,38]. ROS are produced during several processes, including mitochondrial activity in vivo, the oxidation of chemicals and biomolecules, exposure to environmental pollutants such as electrical and UV radiation, and in response to hypoperfusion and reperfusion followed by ischemia [34,36,39]. These ROS are normally detoxified by a variety of antioxidant enzymatic scavengers, such as superoxide dismutase (SOD), catalase, glutathione S-transferase, and glutathione peroxidase (GPX).
ROS include both endogenous and exogenous species, and the major endogenous sources of physiologically relevant ROS include different cellular organs such as mitochondria, peroxisomes, and endoplasmic reticula. Exogenous sources of ROS include smoking, ozone exposure, hyperoxia, ionizing radiation, and exposure to heavy metal ions [40,41]. Mitochondria, the primary source of ROS, generate them as a metabolic byproduct. Mitochondrial ROS have been reported to regulate postmetabolic feedback, autophagy, and inflammatory responses [42,43,44]. Most oxygen is metabolized in the mitochondria, rendering mitochondrial DNA (mtDNA) susceptible to free radical damage. mtDNA has the disadvantages of high information density and low repair capacity, and ROS inhibit mitochondrial transcription. The inner mitochondrial membrane is rich in unsaturated fatty acids but is easily deformed by ROS. This susceptibility to damage stems from the unsaturated nature of the fatty acids, making them prone to peroxidation by ROS. Consequently, the oxidative damage in mtDNA gradually accumulates, leading to cell degeneration and death, which is considered to underlie the progression of aging [45].

4. Role of Mitochondrial Oxidative Stress in Hearing Loss

Mitochondria play an important role in ROS production, and genetic mutations affecting mitochondrial function are associated with hereditary hearing loss. Mitochondrial oxidative stress is the common cause of most types of SNHL, including age-related, genetic, and ototoxic drug- and noise-induced hearing loss [46]. Oxidative stress and free radical generation have been shown to contribute to ARHL in inbred mice [47,48,49]. Moreover, superoxide dismutase 1 (SOD1) has been implicated in ROS processing during the oxidative stress response [50]. SOD1 is widely distributed in inner ear tissues, including the spiral ligaments, stria vascularis, and organs of Corti. Notably, SOD1-knockout mice exhibit early progression of ARHL [51]. Similarly, the senescence-accelerated mouse prone 8 (SAMP8) strain, a model for accelerated aging, shows early deafness. Oxidative stress has been implicated in the molecular mechanisms associated with premature cochlear senescence in SAMP8 mice [52]. In these mice, OHCs, spiral ganglion neurons (SGNs), and stria vascularis are reported to gradually degenerate. Moreover, guinea pigs overexpressing catalase in the cochlea display significant protection of hair cells and hearing thresholds after ototoxic treatment [53,54].
The cochlea is extremely susceptible to oxidative stress owing to the high metabolic demands of hair cells in response to sound stimuli. Normally, under physiological conditions, ROS produced in the mitochondria of hair cells are eliminated by the intrinsic antioxidant effects of hair cells. However, under conditions of excessive ROS levels due to external factors, such as noise or ototoxic drugs, the antioxidant defenses of hair cells are compromised, resulting in permanent cochlear degeneration [55,56]. mtDNA is constantly exposed to DNA-damaging agents, similarly to nuclear DNA [57,58]. Owing to its proximity to the electron transport chain and the lack of protective histones, mtDNA is more susceptible to damage from toxic chemicals compared to nuclear DNA [59]. Mutations in mtDNA accumulate and expand during cell division, causing age-related diseases. Oxidative damage to hair cell mtDNA induces mitochondrial dysregulation and triggers apoptosis [60,61]. The activation of the c-Jun N-terminal kinase/mitogen-activated protein kinase (JNK/MAPK) pathway, an apoptotic signaling pathway, has also been observed in OHCs in response to oxidative stress [62]. In addition to apoptosis, ROS generation leads to inflammation and the production of the pro-inflammatory cytokines interleukin-6 [63] and tumor necrosis factor-alpha [64]. The presence of vasoactive lipid peroxidation products, such as isoprostanes, may also contribute to reduced cochlear blood flow associated with excessive noise [65,66]. Noise-induced ischemia and subsequent reperfusion further potentiate ROS [16] (Figure 1).

5. Role of Oxidative Stress in ARHL

ARHL, also known as presbycusis, is characterized by a progressive decline in hearing ability with aging [67,68]. Moreover, self-reported hearing loss can be identified in half of those aged 85 years and older [69]. The incidence of ARHL is expected to increase as the older adult population expands [67,70,71]. Several factors have been suggested to influence the onset and degree of ARHL, including genetic factors; racial differences; a history of noise exposure; smoking; alcohol consumption; and various health complications such as diabetes, cardiovascular disease, sex hormones, arteriosclerosis, and obesity [1]. ARHL is thought to result from the age-related degeneration of the cochlea, with cumulative effects of extrinsic damage (noise and other ototoxic agents) and intrinsic disorders (e.g., systemic diseases) [68]. It has been suggested that a substantial contribution to presbycusis accumulates with low-level damage due to noise and other insults [67]. Schuknecht classified four types of age-related changes in hearing based on human temporal bone pathological specimens and audiograms: (1) sensory presbycusis, involving damage to sensory hair cells; (2) neuronal presbycusis, involving damage to SGNs; (3) metabolic presbycusis, involving damage to stria vascularis and leading to strial atrophy; and (4) mechanical presbycusis, characterized by a thick and stiff basilar membrane and cochlear duct [72]. Most patients with presbycusis present with a mixed pathology, and it has been suggested that the central auditory pathways that contribute to the onset and progression of ARHL may be affected, in addition to peripheral pathology.
It is widely accepted that mitochondria are a major source of ROS and represent a crucial site for ROS-induced oxidative damage and that ROS production increases with age [34,73]. The accumulation of glutathionylated proteins with age is an indicator of protein oxidation resulting from the formation of hydrogen peroxide [74,75,76]. Moreover, increased 4-hydroxynonenal indicates lipid peroxidation resulting mainly from the formation of hydroxyl radicals, whereas the presence of 3-nitrotyrosine suggests a peroxynitrite reaction [77]. In rats, mitochondrial deletions increase with age and are correlated with deafness [78]. Additionally, ARHL is more rapid and severe in SOD-deficient mice, suggesting the importance of these endogenous antioxidants in cochlear hair cell survival [48]. A study exploring oxidative stress in the cochlea of aging male CBA/J mice revealed notable insights, including the accumulation of ROS in different tissues of the aging cochlea. Notably, the timing and extent of these oxidative changes varied across the different tissues, suggesting diverse mechanisms at play. These results indicate that different types of oxidative stress are increased in aging cochlea and that the cellular antioxidant defense system is impaired [47].
Acetyl-l-carnitine and alpha-lipoic acid improve cochlear function by reducing the age-related loss of hearing sensitivity. This effect appears to be related to the ability of mitochondrial metabolites to protect and repair age-related cochlear mtDNA damage by upregulating mitochondrial function and improving the energy production capacity [79]. Lecithin is a polyunsaturated phosphatidylcholine (PPC), a high-energy functional and structural element of all biomembranes. PPCs are important antioxidants that protect cell membranes from ROS-induced damage and play a scavenging role in the activation of enzymes such as SOD and glutathione. mtDNA mutations tend to accumulate more frequently than chromosomal DNA mutations, and the same mechanism has been suggested for ARHL in a mouse model of ARHL [80]. Thus, ROS-induced damage to mtDNA may lead to reduced mitochondrial function in the cochlea and consequent hearing loss [81]. In C57BL/6J mice with the deletion of the mitochondrial pro-apoptotic gene Bak, age-related apoptotic cell death in cochlear spiral ganglion neurons and hair cells is reduced, and ARHL is prevented. Thus, the induction of a Bak-dependent mitochondrial apoptosis program in response to oxidative stress is an important mechanism of action of ARHL in C57BL/6J mice [82].

6. Role of Oxidative Stress on NIHL

NIHL is the second most common cause of SNHL after ARHL, affecting approximately 5% of the global population [26,83]. NIHL can be unilateral or bilateral, and the hearing loss can be transient or permanent [84]. In mammals, sensory hair cells, once damaged, cannot regenerate. Therefore, the noise-induced degeneration of these hair cells and nerves can lead to permanent hearing loss [85]. Studies suggest that OHCs are the primary target of noise-induced damage, which is exacerbated by the loss of OHCs in basal cochlear lesions [86]. Various mechanisms have been postulated as the main causes of noise-induced inner ear damage, including mechanical damage [87], reduced blood flow and hypoxia [88,89,90], glutamate-induced excitotoxicity [91], and free radical-induced tissue damage [89,92,93,94]. Susceptibility to noise can vary among individuals, owing to a mixture of genetic and environmental factors. The unmodifiable risk factors for hearing loss include age, genetics, sex, and race [28,95,96]. Several modifiable risk factors, including failure to use hearing protection [97], smoking [98], physical inactivity [99], diabetes, and heart disease [100], have been associated with an increased risk of NIHL [28].
Excessive ROS production is a widely accepted mediator of noise-induced damage to the cochlea [101,102,103]. ROS production is noted immediately after noise exposure and persists for 7–10 days thereafter, expanding from the basal to the apical direction of the organ of Corti and increasing the area of necrosis and apoptosis [92,104]. Ohlemiller et al. analyzed hydroxyl (OH) radicals in the cochlea and reported an almost 4-fold increase in OH 1–2 h after noise exposure [101]. Yamane et al. further demonstrated this noise-induced increase in free radicals localized to the stria vascularis [93].
Lipid peroxidation products generated by ROS induce apoptosis, and vasoactive lipid peroxidation products, such as isoprostanes, reduce cochlear blood flow [105,106]. Noise-induced ischemia and subsequent reperfusion further promote ROS production [101]. ROS production in the cochlea can also lead to the release of inflammatory cytokines, causing further damage [63,107,108]. NAD(P)H oxidase (NOX), a membrane-bound protein that transfers electrons to oxygen molecules across the cell membrane, has been implicated in noise-induced cellular stress. It may also contribute to ROS production in NIHL, as a reduction in permanent hearing loss has been reported after the intracochlear administration of NOX inhibitors under noise-induced cellular stress [109,110,111,112]. A similar mechanism involving reactive oxygen species has been reported for DIHL [30,113,114,115].
Animal studies have demonstrated genetic susceptibility to NIHL. One strain of mice (C57BL/6J) with ARHL is more susceptible to noise than other strains [116,117,118]. Several knockout mice, including those for SOD1 [119], GPX1 [120], and plasma membrane calcium-ATPase pump isoform 2 [121], have been shown to be more sensitive to noise than their wild-type littermates. A study using knockout mice reported genetic deficits that disrupt various pathways and structures within the cochlea, thereby increasing the noise sensitivity of the inner ear [38].

7. Role of Oxidative Stress on DIHL

Ototoxic drug exposure is another major cause of SNHL. While there are several classes of drugs that are ototoxic, the most clinically important ototoxicity-associated drugs are platinum-based anticancer drugs such as cisplatin and carboplatin and aminoglycoside antibiotics, which are known to cause irreversible hearing loss [29]. Both classes of drugs primarily damage hair cells in the organ of Corti by producing ROS via apoptotic pathways [122].
The platinum-based drugs cisplatin, carboplatin, and oxaliplatin are among the most widely used anticancer chemotherapeutics. Despite their potential to treat cancer and prolong survival, platinum-based drugs often cause side effects including hearing loss [123]. Cisplatin toxicity in the inner ear is characterized by progressive, bilateral, irreversible hearing loss, particularly in the high frequencies [124]. Chronic changes due to these disorders are seen in the OHCs, stria vascularis and SGCs of the inner ear [125,126,127]. The mechanism has been reported to involve increased ROS levels in the cochlea and the induction of cell death by apoptosis [128,129]. Kopke et al. investigated the antioxidant defense system of the organ of Corti using an in vitro model in rats [130]. Their findings, and those of others, suggest that cisplatin causes damage to hair cells that is associated with the production of ROS, the depletion of intracellular GSH, and interference with antioxidant enzymes in the cochlea [17,131]. Mitochondrial apoptotic pathways have also been implicated in cisplatin ototoxicity, and the inhibition of cell death may be a potential strategy for treating cisplatin-related ototoxicity [132].
Aminoglycosides are among the most commonly used antibiotics to treat infectious diseases; however, they are associated with serious side effects, including nephrotoxicity and irreversible hearing loss [133]. While nephrotoxic side effects are generally reversible, severe ototoxic damage is often not and may result in permanent hearing loss, vestibular dysfunction, or both [134]. One of the major factors in aminoglycoside-induced cochlear damage is oxidative stress via ROS [135]. Gentamicin is known to reduce the mitochondrial membrane potential of OHCs. This leads to the production of NADPH in the OHCs, which increases ROS and induces apoptosis [136]. Aminoglycosides tend to accumulate in the mitochondria of hair cells, which can lead to a pool of ROS and cause hearing loss [137]. The 1555A>G mitochondrial DNA mutation is known to cause hereditary hearing loss associated with aminoglycoside hypersusceptibility [138]. In addition to the A1555G mutation, other mitochondrial DNA mutations associated with hearing loss due to aminoglycoside hypersusceptivity have recently been reported, but the details of their mechanisms of action remain unclear [139].

8. Mechanisms of Ischemia–Reperfusion Injury

ROS play an important role in ischemia–reperfusion injury; they are produced during ischemia–reperfusion, inducing organ damage [140,141]. ROS production is intricately orchestrated through the following various mechanisms: (i) Xanthine oxidase: Xanthine produces oxidase from hypoxanthine with xanthine, which is produced via the catabolism of ATP during ischemia. (ii) NOX: NOX is normally divided into a membrane-bound subunit and a cytoplasmic subunit and binds during ischemia–reperfusion. (iii) Mitochondria: During ischemia, the environment within the mitochondria is altered owing to the failure of the electron-transfer system. During reperfusion, the electron-transfer system is reactivated, resulting in electron leakage and the production of ROS from oxygen. (iv) Endothelial nitric oxide synthase (eNOS): Normally, eNOS binds to tetrahydrobiopterin to synthesize NO. However, during ischemia–reperfusion, 7,8-tetrahydrobiopterin binds to NO synthase, and ROS is produced from oxygen. ROS produced by these mechanisms acts on the mitochondrial permeability transition pore (mPTP). The mPTP is normally closed but can be opened by excess ROS generated during ischemia–reperfusion or by low ATP levels [142]. The opening of the mPTP disrupts the normal movement of molecules within the mitochondrial matrix and between the mitochondria and cytoplasm. This can lead to the mitochondria swelling and collapsing [143], ultimately causing a loss of function. Consequently, energy production in the mitochondria is insufficient, the activity of calcium ATPases in the plasma membrane and endoplasmic reticulum is reduced, and intracellular calcium concentration homeostasis is disrupted [144,145]. The ototoxicity of NO is known to be greatly enhanced by its reaction with other toxic agents, especially superoxide, in ischemia–reperfusion injury to form peroxynitrite [146]. In a study on gerbils, transient ischemia caused a remarkable increase in NO production in perilymph, which might be attributable to the inducible NOS pathway [147]. In the same animal model, the antioxidant molecular hydrogen was effective against hearing loss induced by cochlear ischemia, which is thought to be the main cause of idiopathic SNHL [148].

9. Potential of Antioxidants for the Treatment of Sensorineural Hearing Loss

Antioxidants have the potential to both preserve and restore hearing function by mitigating mtDNA mutations, as demonstrated in experiments using C57BL/6 mice, a common model for ARHL. Examples of such antioxidants include vitamin C, vitamin E, and melatonin [38,82,149]. Antioxidants are broadly classified as endogenous, produced in vivo, or exogenous, supplied externally. Bipolar antioxidants, such as alpha-lipoic acid, act as antioxidants and restore the antioxidant effects of glutathione, vitamin A, vitamin C, and vitamin E [150]. The administration of alpha-lipoic acid prevents NIHL and carboplatin-induced hearing loss in animals [151,152,153]. N-acetyl-L-cysteine (NAC), a precursor of glutathione, is an endogenous antioxidant enzyme with antioxidant properties [154] that has been reported to reduce the ototoxic effects of noise exposure in animal models [155,156,157,158,159].
Water-soluble antioxidants include methionine, vitamin C, carnitine, riboflavin, niacin, folic acid, polyphenols, and catechins. β-carotene, vitamin E, astaxanthin, and coenzyme Q10 (CoQ10) are widely known as fat-soluble antioxidants and are used as dietary supplements [150]. D-methionine reduces noise-induced oxidative stress and cochlear dysfunction in mice [160]. Folic acid supplementation reduces hearing loss by reducing oxidative stress and homocysteine levels [161]. Vitamin E supplementation reduces cochlear damage in NIHL [162,163], cisplatin [164,165], and gentamicin [166,167]. CoQ10 [168], synthetic analogs of CoQ10, idebenone [169], and soluble CoQ10 are effective in reducing hypoxia-induced hearing loss and NIHL [170]. Studies in guinea pig models of NIHL have shown that combination therapy with magnesium and antioxidants, such as vitamins A, C, and E, may have a protective effect, suggesting potential synergy [171]. Notably, calorie restriction remains the only reliable method for slowing aging in mammals, with numerous reports demonstrating its effectiveness in suppressing age-related diseases and extending lifespan [172,173]. Someya et al. reported that SIRT3, a member of the mammalian sirtuin family localized in the mitochondria, is essential for the suppression of ARHL in mice by calorie restriction [174]. These results suggest that mitochondria-localized mammalian sirtuins play an important role in the suppression of age-related cochlear cell death and ARHL induced by calorie restriction.
As most evidence for the benefits of antioxidants against hearing loss is based on animal studies, their role in humans remains unclear. Prospective studies have not indicated that dietary supplementation with vitamins A, C, or E slows ARHL progression [175,176,177]. Further clinical trials are required to confirm the protective effects of antioxidants against different types of SNHL (Table 1).

10. Conclusions

In recent decades, research has revealed the relationship between ROS and ARHL, as well as between ROS and sensorineural hearing loss caused by noise, ischemia, or ototoxic drugs. The urgency for new hearing loss therapies is rising, fueled by evidence from several studies. The cochlea, which plays a major role in auditory function, requires constant high-energy metabolism and is, therefore, extremely vulnerable to oxidative stress, particularly in the mitochondria. While the vast body of literature on this subject is too extensive to be covered comprehensively, the key findings and insights are included in this review. The potential of antioxidants in the treatment of hearing loss has been demonstrated in several animal studies, but results from clinical studies are still insufficient. Randomized controlled clinical trials are required to demonstrate the efficacy of antioxidants in the treatment of hearing loss. Additionally, age-related and noise-, drug-, and ischemia-induced hearing loss have a common cause in the form of ROS, which may prove relevant to prevent the disease. We hope that further clarification of the pathology of hearing loss will lead to its enhanced prevention, as well as that of associated dementia.

Author Contributions

M.T.: writing, N.H., H.I. and F.Y.: review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by TIMA Establishment (Liechtenstein) (grant number 20170101). All patents and trademarks of Twendee X® are the sole property of TIMA Establishment (Liechtenstein).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

F.Y. and H.I. are employees of Gifu University. The Division of Antioxidant Research is a laboratory established at the Life Science Research Centre of Gifu University based on research funds from the TIMA Establishment (Liechtenstein). The sponsor had no role in the writing or publication of the manuscript.

References

  1. Yamasoba, T.; Someya, S.; Yamada, C.; Weindruch, R.; Prolla, T.A.; Tanokura, M. Role of Mitochondrial Dysfunction and Mitochondrial DNA Mutations in Age-Related Hearing Loss. Hear. Res. 2007, 226, 185–193. [Google Scholar] [CrossRef] [PubMed]
  2. Lin, F.R.; Yaffe, K.; Xia, J.; Xue, Q.L.; Harris, T.B.; Purchase-Helzner, E.; Satterfield, S.; Ayonayon, H.N.; Ferrucci, L.; Simonsick, E.M.; et al. Hearing Loss and Cognitive Decline in Older Adults. JAMA Intern. Med. 2013, 173, 293–299. [Google Scholar] [CrossRef] [PubMed]
  3. Guo, L.; Cao, W.; Niu, Y.; He, S.; Chai, R.; Yang, J. Autophagy Regulates the Survival of Hair Cells and Spiral Ganglion Neurons in Cases of Noise, Ototoxic Drug, and Age-Induced Sensorineural Hearing Loss. Front. Cell. Neurosci. 2021, 15, 760422. [Google Scholar] [CrossRef] [PubMed]
  4. Chern, A.; Golub, J.S. Age-Related Hearing Loss and Dementia. Alzheimer Dis. Assoc. Disord. 2019, 33, 285–290. [Google Scholar] [CrossRef] [PubMed]
  5. Livingston, G.; Sommerlad, A.; Orgeta, V.; Costafreda, S.G.; Huntley, J.; Ames, D.; Ballard, C.; Banerjee, S.; Burns, A.; Co-hen-Mansfield, J.; et al. Dementia prevention, intervention, and care. Lancet 2017, 390, 2673–2734. [Google Scholar] [CrossRef] [PubMed]
  6. Bowl, M.R.; Dawson, S.J. Age-Related Hearing Loss. Cold Spring Harb. Perspect. Med. 2019, 9, a033217. [Google Scholar] [CrossRef] [PubMed]
  7. Griffiths, T.D.; Lad, M.; Kumar, S.; Holmes, E.; McMurray, B.; Maguire, E.A.; Billig, A.J.; Sedley, W. How Can Hearing Loss Cause Dementia? Neuron 2020, 108, 401–412. [Google Scholar] [CrossRef] [PubMed]
  8. World Health Organization. World Report on Hearing—Executive Summary; World Health Organization: Geneva, Switzerland, 2021. [Google Scholar]
  9. Škerková, M.; Kovalová, M.; Rychlý, T.; Tomášková, H.; Šlachtová, H.; Čada, Z.; Maďar, R.; Mrázková, E. Extended High-Frequency Audiometry: Hearing Thresholds in Adults. Eur. Arch. Otorhinolaryngol. 2023, 280, 565–572. [Google Scholar] [CrossRef] [PubMed]
  10. Kociszewska, D.; Vlajkovic, S. Age-Related Hearing Loss: The Link Between Inflammaging, Immunosenescence, and Gut Dysbiosis. Int. J. Mol. Sci. 2022, 23, 7348. [Google Scholar] [CrossRef]
  11. Harman, D. Aging: A Theory Based on Free Radical and Radiation Chemistry. J. Gerontol. 1956, 11, 298–300. [Google Scholar] [CrossRef]
  12. Martemucci, G.; Costagliola, C.; Mariano, M.; D’Andrea, L.; Napolitano, P.; D’Alessandro, A.G. Free Radical Properties, Source and Targets, Antioxidant Consumption and Health. Oxygen 2022, 2, 48–78. [Google Scholar] [CrossRef]
  13. Perez-Campo, R.; López-Torres, M.; Cadenas, S.; Rojas, C.; Barja, G. The Rate of Free Radical Production as a Determinant of the Rate of Aging: Evidence from the Comparative Approach. J. Comp. Physiol. B 1998, 168, 149–158. [Google Scholar] [CrossRef] [PubMed]
  14. Dinh, C.T.; Goncalves, S.; Bas, E.; Van De Water, T.R.; Zine, A. Molecular Regulation of Auditory Hair Cell Death and Approaches to Protect Sensory Receptor Cells and/or Stimulate Repair Following Acoustic Trauma. Front. Cell. Neurosci. 2015, 9, 96. [Google Scholar] [CrossRef] [PubMed]
  15. Böttger, E.C.; Schacht, J. The Mitochondrion: A Perpetrator of Acquired Hearing Loss. Hear. Res. 2013, 303, 12–19. [Google Scholar] [CrossRef] [PubMed]
  16. Wong, A.C.; Ryan, A.F. Mechanisms of Sensorineural Cell Damage, Death and Survival in the Cochlea. Front. Aging Neurosci. 2015, 7, 58. [Google Scholar] [CrossRef] [PubMed]
  17. Fujimoto, C.; Yamasoba, T. Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review. Antioxidants 2019, 8, 109. [Google Scholar] [CrossRef] [PubMed]
  18. Hudspeth, A.J. How Hearing Happens. Neuron 1997, 19, 947–950. [Google Scholar] [CrossRef]
  19. Wangemann, P. Supporting Sensory Transduction: Cochlear Fluid Homeostasis and the Endocochlear Potential. J. Physiol. 2006, 576, 11–21. [Google Scholar] [CrossRef]
  20. Schwander, M.; Kachar, B.; Müller, U. Review Series: The Cell Biology of Hearing Review Series. J. Cell Biol. 2010, 190, 9–20. [Google Scholar] [CrossRef]
  21. Goutman, J.D.; Elgoyhen, A.B.; Gómez-Casati, M.E. Cochlear Hair Cells: The Sound-Sensing Machines. FEBS Lett. 2015, 589, 3354–3361. [Google Scholar] [CrossRef]
  22. Marcotti, W. Functional Assembly of Mammalian Cochlear Hair Cells. Exp. Physiol. 2012, 97, 438–451. [Google Scholar] [CrossRef] [PubMed]
  23. Von Békésy, G. Experiments in Hearing; McGraw-Hill: New York, NY, USA, 1960. [Google Scholar]
  24. Fuchs, P.A.; Glowatzki, E.; Moser, T. The Afferent Synapse of Cochlear Hair Cells. Curr. Opin. Neurobiol. 2003, 13, 452–458. [Google Scholar] [CrossRef] [PubMed]
  25. Raphael, Y.; Altschuler, R.A. Structure and Innervation of the Cochlea. Brain Res. Bull. 2003, 60, 397–422. [Google Scholar] [CrossRef] [PubMed]
  26. Natarajan, N.; Batts, S.; Stankovic, K.M. Noise-Induced Hearing Loss. J. Clin. Med. 2023, 12, 2347. [Google Scholar] [CrossRef] [PubMed]
  27. Le Prell, C.G. Prevention of Noise-Induced Hearing Loss Using Investigational Medicines for the Inner Ear: Previous Trial Outcomes Should Inform Future Trial Design. Antioxid. Redox Signal. 2022, 36, 1171–1202. [Google Scholar] [CrossRef] [PubMed]
  28. Daniel, E. Noise and Hearing Loss: A Review. J. Sch. Health 2007, 77, 225–231. [Google Scholar] [CrossRef] [PubMed]
  29. Huth, M.E.; Ricci, A.J.; Cheng, A.G. Mechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection. Int. J. Otolaryngol. 2011, 2011, 937861. [Google Scholar] [CrossRef] [PubMed]
  30. Chirtes, F.; Albu, S. Prevention and Restoration of Hearing Loss Associated with the Use of Cisplatin. BioMed Res. Int. 2014, 2014, 925485. [Google Scholar] [CrossRef] [PubMed]
  31. Crane, R.A.; Camilon, M.; Nguyen, S.; Meyer, T.A. Steroids for Treatment of Sudden Sensorineural Hearing Loss: A Meta-Analysis of Randomized Controlled Trials. Laryngoscope 2015, 125, 209–217. [Google Scholar] [CrossRef]
  32. Conlin, A.E.; Parnes, L.S. Treatment of Sudden Sensorineural Hearing Loss: I. A Systematic Review. Arch. Otolaryngol. Head Neck Surg. 2007, 133, 573–581. [Google Scholar] [CrossRef]
  33. Lushchak, V.I. Free Radicals, Reactive Oxygen Species, Oxidative Stress and Its Classification. Chem. Biol. Interact. 2014, 224, 164–175. [Google Scholar] [CrossRef] [PubMed]
  34. Balaban, R.S.; Nemoto, S.; Finkel, T. Mitochondria, Oxidants, and Aging. Cell 2005, 120, 483–495. [Google Scholar] [CrossRef] [PubMed]
  35. Lin, M.T.; Beal, M.F. Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases. Nature 2006, 443, 787–795. [Google Scholar] [CrossRef] [PubMed]
  36. Turrens, J.F. Mitochondrial Formation of Reactive Oxygen Species. J. Physiol. 2003, 552, 335–344. [Google Scholar] [CrossRef] [PubMed]
  37. Halliwell, B.; Gutteridge, J.M.; Cross, C.E. Free Radicals, Antioxidants, and Human Disease: Where Are We Now? J. Lab. Clin. Med. 1992, 119, 598–620. [Google Scholar] [PubMed]
  38. Seidman, M.D. Effects of Dietary Restriction and Antioxidants on Presbyacusis. Laryngoscope 2000, 110, 727–738. [Google Scholar] [CrossRef] [PubMed]
  39. Sena, L.A.; Chandel, N.S. Physiological Roles of Mitochondrial Reactive Oxygen Species. Mol. Cell 2012, 48, 158–167. [Google Scholar] [CrossRef] [PubMed]
  40. Phaniendra, A.; Jestadi, D.B.; Periyasamy, L. Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases. Indian J. Clin. Biochem. 2015, 30, 11–26. [Google Scholar] [CrossRef] [PubMed]
  41. Birben, E.; Sahiner, U.M.; Sackesen, C.; Erzurum, S.; Kalayci, O. Oxidative Stress and Antioxidant Defense. World Allergy Organ. J. 2012, 5, 9–19. [Google Scholar] [CrossRef]
  42. Miao, L.; Zhang, J.; Yin, L.; Pu, Y. Metabolomics Analysis Reveals Alterations in Cochlear Metabolic Profiling in Mice with Noise-Induced Hearing Loss. BioMed Res. Int. 2022, 2022, 9548316. [Google Scholar] [CrossRef]
  43. Schwarz, C.; Stekovic, S.; Wirth, M.; Benson, G.; Royer, P.; Sigrist, S.J.; Pieber, T.; Dammbrueck, C.; Magnes, C.; Eisenberg, T.; et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging 2018, 10, 19–33. [Google Scholar] [CrossRef] [PubMed]
  44. Pekar, T.; Bruckner, K.; Pauschenwein-Frantsich, S.; Gschaider, A.; Oppliger, M.; Willesberger, J.; Ungersbäck, P.; Wendzel, A.; Kremer, A.; Flak, W.; et al. The positive effect of spermidine in older adults suffering from dementia: First results of a 3-month trial. Wien Klin. Wochenschr. 2021, 133, 484–491. [Google Scholar] [CrossRef]
  45. Barja, G. Updating the Mitochondrial Free Radical Theory of Aging: An Integrated View, Key Aspects, and Confounding Concepts. Antioxid. Redox Signal. 2013, 19, 1420–1445. [Google Scholar] [CrossRef] [PubMed]
  46. Kamogashira, T.; Fujimoto, C.; Yamasoba, T. Reactive Oxygen Species, Apoptosis, and Mitochondrial Dysfunction in Hearing Loss. BioMed Res. Int. 2015, 2015, 617207. [Google Scholar] [CrossRef]
  47. Jiang, H.; Talaska, A.E.; Schacht, J.; Sha, S.H. Oxidative Imbalance in the Aging Inner Ear. Neurobiol. Aging 2007, 28, 1605–1612. [Google Scholar] [CrossRef] [PubMed]
  48. McFadden, S.L.; Ding, D.; Salvi, R. Anatomical, Metabolic and Genetic Aspects of Age-Related Hearing Loss in Mice: Aspectos Anatómicos, Metabólicos y Genéticos de la Hipoacusia Relacionada Con la Edad en Ratones. Int. J. Audiol. 2001, 40, 313–321. [Google Scholar] [CrossRef]
  49. Staecker, H.; Zheng, Q.Y.; Van De Water, T.R. Oxidative Stress in Aging in the C57B16/J Mouse Cochlea. Acta Otolaryngol. 2001, 121, 666–672. [Google Scholar] [CrossRef] [PubMed]
  50. Pierson, M.G.; Gray, B.H. Superoxide Dismutase Activity in the Cochlea. Hear. Res. 1982, 6, 141–151. [Google Scholar] [CrossRef] [PubMed]
  51. Keithley, E.M.; Canto, C.; Zheng, Q.Y.; Wang, X.; Fischel-Ghodsian, N.; Johnson, K.R. Cu/Zn Superoxide Dismutase and Age-Related Hearing Loss. Hear. Res. 2005, 209, 76–85. [Google Scholar] [CrossRef]
  52. Menardo, J.; Tang, Y.; Ladrech, S.; Lenoir, M.; Casas, F.; Michel, C.; Bourien, J.; Ruel, J.; Rebillard, G.; Maurice, T.; et al. Oxidative Stress, Inflammation, and Autophagic Stress as the Key Mechanisms of Premature Age-Related Hearing Loss in SAMP8 Mouse Cochlea. Antioxid. Redox Signal. 2012, 16, 263–274. [Google Scholar] [CrossRef]
  53. Kawamoto, K.; Sha, S.H.; Minoda, R.; Izumikawa, M.; Kuriyama, H.; Schacht, J.; Raphael, Y. Antioxidant Gene Therapy Can Protect Hearing and Hair Cells from Ototoxicity. Mol. Ther. 2004, 9, 173–181. [Google Scholar] [CrossRef] [PubMed]
  54. González-González, S. The Role of Mitochondrial Oxidative Stress in Hearing Loss. Neurol. Disord. Therap. 2017, 1, 1–5. [Google Scholar] [CrossRef]
  55. Fujimoto, C.; Yamasoba, T. Oxidative Stresses and Mitochondrial Dysfunction in Age-Related Hearing Loss. Oxid. Med. Cell. Longev. 2014, 2014, 582849. [Google Scholar] [CrossRef] [PubMed]
  56. Chen, B.; Zhong, Y.; Peng, W.; Sun, Y.; Hu, Y.J.; Yang, Y.; Kong, W.J. Increased Mitochondrial DNA Damage and Decreased Base Excision Repair in the Auditory Cortex of d-Galactose-Induced Aging Rats. Mol. Biol. Rep. 2011, 38, 3635–3642. [Google Scholar] [CrossRef] [PubMed]
  57. Druzhyna, N.M.; Wilson, G.L.; LeDoux, S.P. Mitochondrial DNA Repair in Aging and Disease. Mech. Ageing Dev. 2008, 129, 383–390. [Google Scholar] [CrossRef]
  58. Bandy, B.; Davison, A.J. Mitochondrial Mutations May Increase Oxidative Stress: Implications for Carcinogenesis and Aging? Free Radic. Biol. Med. 1990, 8, 523–539. [Google Scholar] [CrossRef] [PubMed]
  59. Ames, B.N.; Shigenaga, M.K.; Hagen, T.M. Oxidants, Antioxidants, and the Degenerative Diseases of Aging. Proc. Natl. Acad. Sci. USA 1993, 90, 7915–7922. [Google Scholar] [CrossRef] [PubMed]
  60. Lee, H.; Yoon, Y. Mitochondrial Fission and Fusion. Biochem. Soc. Trans. 2016, 44, 1725–1735. [Google Scholar] [CrossRef] [PubMed]
  61. Cheng, A.G.; Cunningham, L.L.; Rubel, E.W. Mechanisms of Hair Cell Death and Protection. Curr. Opin. Otolaryngol. Head Neck Surg. 2005, 13, 343–348. [Google Scholar] [CrossRef]
  62. Wang, J.; Ruel, J.; Ladrech, S.; Bonny, C.; van de Water, T.R.; Puel, J.L. Inhibition of the c-Jun N-Terminal Kinase-Mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-Exposed Animals. Mol. Pharmacol. 2007, 71, 654–666. [Google Scholar] [CrossRef]
  63. Wakabayashi, K.; Fujioka, M.; Kanzaki, S.; Okano, H.J.; Shibata, S.; Yamashita, D.; Masuda, M.; Mihara, M.; Ohsugi, Y.; Ogawa, K.; et al. Blockade of Interleukin-6 Signaling Suppressed Cochlear Inflammatory Response and Improved Hearing Impairment in Noise-Damaged Mice Cochlea. Neurosci. Res. 2010, 66, 345–352. [Google Scholar] [CrossRef] [PubMed]
  64. Keithley, E.M.; Wang, X.; Barkdull, G.C. Tumor Necrosis Factor Alpha Can Induce Recruitment of Inflammatory Cells to the Cochlea. Otol. Neurotol. 2008, 29, 854–859. [Google Scholar] [CrossRef] [PubMed]
  65. Thorne, P.R.; Nuttall, A.L.; Scheibe, F.; Miller, J.M. Sound-Induced Artifact in Cochlear Blood Flow Measurements Using the Laser Doppler Flowmeter. Hear. Res. 1987, 31, 229–234. [Google Scholar] [CrossRef] [PubMed]
  66. Seidman, M.D.; Quirk, W.S.; Shirwany, N.A. Mechanisms of Alterations in the Microcirculation of the Cochlea. Ann. N. Y. Acad. Sci. 1999, 884, 226–232. [Google Scholar] [CrossRef] [PubMed]
  67. Gates, G.A.; Mills, J.H. Presbycusis. Lancet 2005, 366, 1111–1120. [Google Scholar] [CrossRef] [PubMed]
  68. Liu, X.Z.; Yan, D. Ageing and Hearing Loss. J. Pathol. 2007, 211, 188–197. [Google Scholar] [CrossRef] [PubMed]
  69. Mulrow, C.D.; Lichtenstein, M.J. Screening for Hearing Impairment in the Elderly: Rationale and Strategy. J. Gen. Intern. Med. 1991, 6, 249–258. [Google Scholar] [CrossRef] [PubMed]
  70. Gratton, M.A.; Vázquez, A.E. Age-Related Hearing Loss: Current Research. Curr. Opin. Otolaryngol. Head Neck Surg. 2003, 11, 367–371. [Google Scholar] [CrossRef] [PubMed]
  71. Roth, T.N.; Hanebuth, D.; Probst, R. Prevalence of Age-Related Hearing Loss in Europe: A Review. Eur. Arch. Otorhinolaryngol. 2011, 268, 1101–1107. [Google Scholar] [CrossRef]
  72. Schuknecht, H.F.; Gacek, M.R. Cochlear Pathology in Presbycusis. Ann. Otol. Rhinol. Laryngol. 1993, 102, 1–16. [Google Scholar] [CrossRef]
  73. Beckman, K.B.; Ames, B.N. The Free Radical Theory of Aging Matures. Physiol. Rev. 1998, 78, 547–581. [Google Scholar] [CrossRef] [PubMed]
  74. Wang, J.; Boja, E.S.; Tan, W.; Tekle, E.; Fales, H.M.; English, S.; Mieyal, J.J.; Chock, P.B. Reversible Glutathionylation Regulates Actin Polymerization in A431 Cells. J. Biol. Chem. 2001, 276, 47763–47766. [Google Scholar] [CrossRef] [PubMed]
  75. Rokutan, K.; Johnston, R.B., Jr.; Kawai, K. Oxidative Stress Induces S-thiolation of Specific Proteins in Cultured Gastric Mucosal Cells. Am. J. Physiol. 1994, 266, G247–G254. [Google Scholar] [CrossRef] [PubMed]
  76. Chai, Y.C.; Ashraf, S.S.; Rokutan, K.; Johnston, R.B., Jr.; Thomas, J.A. S-thiolation of Individual Human Neutrophil Proteins Including Actin by Stimulation of the Respiratory Burst: Evidence Against a Role for Glutathione Disulfide. Arch. Biochem. Biophys. 1994, 310, 273–281. [Google Scholar] [CrossRef] [PubMed]
  77. Shin, C.M.; Chung, Y.H.; Kim, M.J.; Lee, E.Y.; Kim, E.G.; Cha, C.I. Age-Related Changes in the Distribution of Nitrotyrosine in the Cerebral Cortex and Hippocampus of Rats. Brain Res. 2002, 931, 194–199. [Google Scholar] [CrossRef] [PubMed]
  78. Seidman, M.D.; Bai, U.; Khan, M.J.; Quirk, W.S. Mitochondrial DNA Deletions Associated with Aging and Presbyacusis. Arch. Otolaryngol. Head Neck Surg. 1997, 123, 1039–1045. [Google Scholar] [CrossRef] [PubMed]
  79. Seidman, M.D.; Khan, M.J.; Bai, U.; Shirwany, N.; Quirk, W.S. Biologic Activity of Mitochondrial Metabolites on Aging and Age-Related Hearing Loss. Am. J. Otol. 2000, 21, 161–167. [Google Scholar] [CrossRef] [PubMed]
  80. Crawley, B.K.; Keithley, E.M. Effects of Mitochondrial Mutations on Hearing and Cochlear Pathology with Age. Hear. Res. 2011, 280, 201–208. [Google Scholar] [CrossRef] [PubMed]
  81. Davis, R.R.; Kuo, M.W.; Stanton, S.G.; Canlon, B.; Krieg, E.; Alagramam, K.N. N-acetyl L-cysteine Does Not Protect Against Premature Age-Related Hearing Loss in C57BL/6J Mice: A Pilot Study. Hear. Res. 2007, 226, 203–208. [Google Scholar] [CrossRef]
  82. Someya, S.; Xu, J.; Kondo, K.; Ding, D.; Salvi, R.J.; Yamasoba, T.; Rabinovitch, P.S.; Weindruch, R.; Leeuwenburgh, C.; Tanokura, M.; et al. Age-Related Hearing Loss in C57BL/6J Mice Is Mediated by Bak-Dependent Mitochondrial Apoptosis. Proc. Natl. Acad. Sci. USA 2009, 106, 19432–19437. [Google Scholar] [CrossRef]
  83. Wilson, B.S.; Tucci, D.L.; Merson, M.H.; O’Donoghue, G.M. Global Hearing Health Care: New Findings and Perspectives. Lancet 2017, 390, 2503–2515. [Google Scholar] [CrossRef] [PubMed]
  84. Liberman, M.C. Noise-Induced Hearing Loss: Permanent Versus Temporary Threshold Shifts and the Effects of Hair Cell Versus Neuronal Degeneration. Adv. Exp. Med. Biol. 2016, 875, 1–7. [Google Scholar] [CrossRef] [PubMed]
  85. Mazurek, B.; Olze, H.; Haupt, H.; Szczepek, A.J. The More the Worse: The Grade of Noise-Induced Hearing Loss Associates with the Severity of Tinnitus. Int. J. Environ. Res. Public Health 2010, 7, 3071–3079. [Google Scholar] [CrossRef]
  86. Wu, P.Z.; O’Malley, J.T.; de Gruttola, V.; Liberman, M.C. Primary Neural Degeneration in Noise-Exposed Human Cochleas: Correlations with Outer Hair Cell Loss and Word-Discrimination Scores. J. Neurosci. 2021, 41, 4439–4447. [Google Scholar] [CrossRef]
  87. Spoendlin, H. Primary Structural Changes in the Organ of Corti After Acoustic Overstimulation. Acta Otolaryngol. 1971, 71, 166–176. [Google Scholar] [CrossRef] [PubMed]
  88. Thorne, P.R.; Nuttall, A.L. Laser Doppler Measurements of Cochlear Blood Flow During Loud Sound Exposure in the Guinea Pig. Hear. Res. 1987, 27, 1–10. [Google Scholar] [CrossRef]
  89. Le Prell, C.G.; Yamashita, D.; Minami, S.B.; Yamasoba, T.; Miller, J.M. Mechanisms of Noise-Induced Hearing Loss Indicate Multiple Methods of Prevention. Hear. Res. 2007, 226, 22–43. [Google Scholar] [CrossRef]
  90. Quirk, W.S.; Avinash, G.; Nuttall, A.L.; Miller, J.M. The Influence of Loud Sound on Red Blood Cell Velocity and Blood Vessel Diameter in the Cochlea. Hear. Res. 1992, 63, 102–107. [Google Scholar] [CrossRef]
  91. Sahley, T.L.; Anderson, D.J.; Hammonds, M.D.; Chandu, K.; Musiek, F.E. Evidence for a Dynorphin-Mediated Inner Ear Immune/Inflammatory Response and Glutamate-Induced Neural Excitotoxicity: An Updated Analysis. J. Neurophysiol. 2019, 122, 1421–1460. [Google Scholar] [CrossRef]
  92. Henderson, D.; Bielefeld, E.C.; Harris, K.C.; Hu, B.H. The Role of Oxidative Stress in Noise-Induced Hearing Loss. Ear Hear. 2006, 27, 1–19. [Google Scholar] [CrossRef]
  93. Yamane, H.; Nakai, Y.; Takayama, M.; Iguchi, H.; Nakagawa, T.; Kojima, A. Appearance of Free Radicals in the Guinea Pig Inner Ear After Noise-Induced Acoustic Trauma. Eur. Arch. Otorhinolaryngol. 1995, 252, 504–508. [Google Scholar] [CrossRef] [PubMed]
  94. Borg, E.; Canlon, B.; Engström, B. Noise-Induced Hearing Loss. Literature Review and Experiments in Rabbits. Morphological and Electrophysiological Features, Exposure Parameters and Temporal Factors, Variability and Interactions. Scand. Audiol. Suppl. 1995, 40, 1–147. [Google Scholar] [PubMed]
  95. Klein, B.E.; Cruickshanks, K.J.; Nondahl, D.M.; Klein, R.; Dalton, D.S. Cataract and Hearing Loss in a Population-Based Study: The Beaver Dam Studies. Am. J. Ophthalmol. 2001, 132, 537–543. [Google Scholar] [CrossRef] [PubMed]
  96. Helzner, E.P.; Cauley, J.A.; Pratt, S.R.; Wisniewski, S.R.; Zmuda, J.M.; Talbott, E.O.; de Rekeneire, N.; Harris, T.B.; Rubin, S.M.; Simonsick, E.M.; et al. Race and Sex Differences in Age-Related Hearing Loss: The Health, Aging and Body Composition Study. J. Am. Geriatr. Soc. 2005, 53, 2119–2127. [Google Scholar] [CrossRef] [PubMed]
  97. Widén, S.E.; Erlandsson, S.I. The Influence of Socio-economic Status on Adolescent Attitude to Social Noise and Hearing Protection. Noise Health 2004, 7, 59–70. [Google Scholar] [PubMed]
  98. Cruickshanks, K.J.; Klein, R.; Klein, B.E.K.; Wiley, T.L.; Nondahl, D.M.; Tweed, T.S. Cigarette Smoking and Hearing Loss: The Epidemiology of Hearing Loss Study. JAMA 1998, 279, 1715–1719. [Google Scholar] [CrossRef] [PubMed]
  99. Kolkhorst, F.W.; Smaldino, J.J.; Wolf, S.C.; Battani, L.R.; Plakke, B.L.; Huddleston, S.; Hensley, L.D. Influence of Fitness on Susceptibility to Noise-Induced Temporary Threshold Shift. Med. Sci. Sports Exerc. 1998, 30, 289–293. [Google Scholar] [CrossRef] [PubMed]
  100. Lusk, S.L.; Hagerty, B.M.; Gillespie, B.; Caruso, C.C. Chronic Effects of Workplace Noise on Blood Pressure and Heart Rate. Arch. Environ. Health 2002, 57, 273–281. [Google Scholar] [CrossRef] [PubMed]
  101. Ohlemiller, K.K.; Wright, J.S.; Dugan, L.L. Early Elevation of Cochlear Reactive Oxygen Species Following Noise Exposure. Audiol. Neurootol. 1999, 4, 229–236. [Google Scholar] [CrossRef]
  102. Cobley, J.N. Mechanisms of Mitochondrial ROS Production in Assisted Reproduction: The Known, the Unknown, and the Intriguing. Antioxidants 2020, 9, 933. [Google Scholar] [CrossRef]
  103. Zhang, W.; Xiong, H.; Pang, J.; Su, Z.; Lai, L.; Lin, H.; Jian, B.; He, W.; Yang, H.; Zheng, Y. Nrf2 Activation Protects Auditory Hair Cells from Cisplatin-Induced Ototoxicity Independent on Mitochondrial ROS Production. Toxicol. Lett. 2020, 331, 1–10. [Google Scholar] [CrossRef]
  104. Yamashita, D.; Jiang, H.Y.; Schacht, J.; Miller, J.M. Delayed Production of Free Radicals Following Noise Exposure. Brain Res. 2004, 1019, 201–209. [Google Scholar] [CrossRef] [PubMed]
  105. Miller, J.M.; Brown, J.N.; Schacht, J. 8-iso-Prostaglandin F(2alpha), a Product of Noise Exposure, Reduces Inner Ear Blood Flow. Audiol. Neurootol. 2003, 8, 207–221. [Google Scholar] [CrossRef] [PubMed]
  106. Ohinata, Y.; Miller, J.M.; Altschuler, R.A.; Schacht, J. Intense Noise Induces Formation of Vasoactive Lipid Peroxidation Products in the Cochlea. Brain Res. 2000, 878, 163–173. [Google Scholar] [CrossRef] [PubMed]
  107. Fujioka, M.; Kanzaki, S.; Okano, H.J.; Masuda, M.; Ogawa, K.; Okano, H. Proinflammatory Cytokines Expression in Noise-Induced Damaged Cochlea. J. Neurosci. Res. 2006, 83, 575–583. [Google Scholar] [CrossRef] [PubMed]
  108. Tornabene, S.V.; Sato, K.; Pham, L.; Billings, P.; Keithley, E.M. Immune Cell Recruitment Following Acoustic Trauma. Hear. Res. 2006, 222, 115–124. [Google Scholar] [CrossRef] [PubMed]
  109. Wang, Y.; Hirose, K.; Liberman, M.C. Dynamics of Noise-Induced Cellular Injury and Repair in the Mouse Cochlea. J. Assoc. Res. Otolaryngol. 2002, 3, 248–268. [Google Scholar] [CrossRef] [PubMed]
  110. Ohinata, Y.; Miller, J.M.; Schacht, J. Protection from Noise-Induced Lipid Peroxidation and Hair Cell Loss in the Cochlea. Brain Res. 2003, 966, 265–273. [Google Scholar] [CrossRef]
  111. Duan, M.; Qiu, J.; Laurell, G.; Olofsson, A.; Counter, S.A.; Borg, E. Dose and Time-Dependent Protection of the Antioxidant N-L-acetylcysteine Against Impulse Noise Trauma. Hear. Res. 2004, 192, 1–9. [Google Scholar] [CrossRef]
  112. Kopke, R.D.; Weisskopf, P.A.; Boone, J.L.; Jackson, R.L.; Wester, D.C.; Hoffer, M.E.; Lambert, D.C.; Charon, C.C.; Ding, D.L.; McBride, D. Reduction of Noise-Induced Hearing Loss Using L-NAC and Salicylate in the Chinchilla. Hear. Res. 2000, 149, 138–146. [Google Scholar] [CrossRef]
  113. Mukherjea, D.; Ghosh, S.; Bhatta, P.; Sheth, S.; Tupal, S.; Borse, V.; Brozoski, T.; Sheehan, K.E.; Rybak, L.P.; Ramkumar, V.V. Early Investigational Drugs for Hearing Loss. Expert Opin. Investig. Drugs 2015, 24, 201–217. [Google Scholar] [CrossRef] [PubMed]
  114. Hammill, T.L.; Campbell, K.C. Protection for Medication-Induced Hearing Loss: The State of the Science. Int. J. Audiol. 2018, 57, S67–S75. [Google Scholar] [CrossRef] [PubMed]
  115. Ramkumar, V.; Mukherjea, D.; Dhukhwa, A.; Rybak, L.P. Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity. Antioxidants 2021, 10, 1919. [Google Scholar] [CrossRef] [PubMed]
  116. Li, H.S. Influence of Genotype and Age on Acute Acoustic Trauma and Recovery in CBA/Ca and C57BL/6J Mice. Acta Otolaryngol. 1992, 112, 956–967. [Google Scholar] [CrossRef] [PubMed]
  117. Erway, L.C.; Shiau, Y.W.; Davis, R.R.; Krieg, E.F. Genetics of Age-Related Hearing Loss in Mice. III. Susceptibility of Inbred and F1 Hybrid Strains to Noise-Induced Hearing Loss. Hear. Res. 1996, 93, 181–187. [Google Scholar] [CrossRef] [PubMed]
  118. Davis, R.R.; Newlander, J.K.; Ling, X.; Cortopassi, G.A.; Krieg, E.F.; Erway, L.C. Genetic Basis for Susceptibility to Noise-Induced Hearing Loss in Mice. Hear. Res. 2001, 155, 82–90. [Google Scholar] [CrossRef] [PubMed]
  119. Ohlemiller, K.K.; McFadden, S.L.; Ding, D.L.; Flood, D.G.; Reaume, A.G.; Hoffman, E.K.; Scott, R.W.; Wright, J.S.; Putcha, G.V.; Salvi, R.J. Targeted Deletion of the Cytosolic Cu/Zn-Superoxide Dismutase Gene (Sod1) Increases Susceptibility to Noise-Induced Hearing Loss. Audiol. Neurootol. 1999, 4, 237–246. [Google Scholar] [CrossRef]
  120. Ohlemiller, K.K.; McFadden, S.L.; Ding, D.L.; Lear, P.M.; Ho, Y.S. Targeted Mutation of the Gene for Cellular Glutathione Peroxidase (Gpx1) Increases Noise-Induced Hearing Loss in Mice. J. Assoc. Res. Otolaryngol. 2000, 1, 243–254. [Google Scholar] [CrossRef] [PubMed]
  121. Kozel, P.J.; Davis, R.R.; Krieg, E.F.; Shull, G.E.; Erway, L.C. Deficiency in Plasma Membrane Calcium ATPase Isoform 2 Increases Susceptibility to Noise-Induced Hearing Loss in Mice. Hear. Res. 2002, 164, 231–239. [Google Scholar] [CrossRef]
  122. Schacht, J.; Talaska, A.E.; Rybak, L.P. Cisplatin and Aminoglycoside Antibiotics: Hearing Loss and Its Prevention. Anat. Rec. 2012, 295, 1837–1850. [Google Scholar] [CrossRef]
  123. Oun, R.; Moussa, Y.E.; Wheate, N.J. The Side Effects of Platinum-Based Chemotherapy Drugs: A Review for Chemists. Dalton Trans. 2018, 47, 6645–6653. [Google Scholar] [CrossRef] [PubMed]
  124. Nakai, Y.; Konishi, K.; Chang, K.C.; Ohashi, K.; Morisaki, N.; Minowa, Y.; Morimoto, A. Ototoxicity of the Anticancer Drug Cisplatin. An Experimental Study. Acta Otolaryngol. 1982, 93, 227–232. [Google Scholar] [CrossRef] [PubMed]
  125. Alam, S.A.; Ikeda, K.; Oshima, T.; Suzuki, M.; Kawase, T.; Kikuchi, T.; Takasaka, T. Cisplatin-Induced Apoptotic Cell Death in Mongolian Gerbil Cochlea. Hear. Res. 2000, 141, 28–38. [Google Scholar] [CrossRef] [PubMed]
  126. Lee, J.E.; Nakagawa, T.; Kita, T.; Kim, T.S.; Iguchi, F.; Endo, T.; Shiga, A.; Lee, S.H.; Ito, J. Mechanisms of Apoptosis Induced by Cisplatin in Marginal Cells in Mouse Stria Vascularis. ORL J. Oto-Rhino-Laryngol. Relat. Spec. 2004, 66, 111–118. [Google Scholar] [CrossRef] [PubMed]
  127. Lee, J.E.; Nakagawa, T.; Kim, T.S.; Iguchi, F.; Endo, T.; Dong, Y.; Yuki, K.; Naito, Y.; Lee, S.H.; Ito, J. A Novel Model for Rapid Induction of Apoptosis in Spiral Ganglions of Mice. Laryngoscope 2003, 113, 994–999. [Google Scholar] [CrossRef]
  128. Rybak, L.P.; Whitworth, C.A.; Mukherjea, D.; Ramkumar, V. Mechanisms of Cisplatin-Induced Ototoxicity and Prevention. Hear. Res. 2007, 226, 157–167. [Google Scholar] [CrossRef] [PubMed]
  129. García-Berrocal, J.R.; Nevado, J.; Ramírez-Camacho, R.; Sanz, R.; González-García, J.A.; Sánchez-Rodríguez, C.; Cantos, B.; España, P.; Verdaguer, J.M.; Trinidad Cabezas, A. The Anticancer Drug Cisplatin Induces an Intrinsic Apoptotic Pathway Inside the Inner Ear. Br. J. Pharmacol. 2007, 152, 1012–1020. [Google Scholar] [CrossRef] [PubMed]
  130. Kopke, R.D.; Liu, W.; Gabaizadeh, R.; Jacono, A.; Feghali, J.; Spray, D.; Garcia, P.; Steinman, H.; Malgrange, B.; Ruben, R.J.; et al. Use of Organotypic Cultures of Corti’s Organ to Study the Protective Effects of Antioxidant Molecules on Cisplatin-Induced Damage of Auditory Hair Cells. Am. J. Otol. 1997, 18, 559–571. [Google Scholar] [PubMed]
  131. Rybak, L.P.; Ravi, R.; Somani, S.M. Mechanism of Protection by Diethyldithiocarbamate Against Cisplatin Ototoxicity: Antioxidant System. Fundam. Appl. Toxicol. 1995, 26, 293–300. [Google Scholar] [CrossRef]
  132. Ravi, R.; Somani, S.M.; Rybak, L.P. Mechanism of Cisplatin Ototoxicity: Antioxidant System. Pharmacol. Toxicol. 1995, 76, 386–394. [Google Scholar] [CrossRef]
  133. Forge, A.; Schacht, J. Aminoglycoside Antibiotics. Audiol. Neurootol. 2000, 5, 3–22. [Google Scholar] [CrossRef] [PubMed]
  134. Lerner, S.A.; Schmitt, B.A.; Seligsohn, R.; Matz, G.J. Comparative Study of Ototoxicity and Nephrotoxicity in Patients Randomly Assigned to Treatment with Amikacin or Gentamicin. Am. J. Med. 1986, 80, 98–104. [Google Scholar] [CrossRef] [PubMed]
  135. Noack, V.; Pak, K.; Jalota, R.; Kurabi, A.; Ryan, A.F. An Antioxidant Screen Identifies Candidates for Protection of Cochlear Hair Cells from Gentamicin Toxicity. Front. Cell. Neurosci. 2017, 11, 242. [Google Scholar] [CrossRef] [PubMed]
  136. Dehne, N.; Rauen, U.; de Groot, H.; Lautermann, J. Involvement of the Mitochondrial Permeability Transition in Gentamicin Ototoxicity. Hear. Res. 2002, 169, 47–55. [Google Scholar] [CrossRef] [PubMed]
  137. Marcotti, W.; Van Netten, S.M.; Kros, C.J. The Aminoglycoside Antibiotic Dihydrostreptomycin Rapidly Enters Mouse Outer Hair Cells Through the Mechano-Electrical Transducer Channels. J. Physiol. 2005, 567, 505–521. [Google Scholar] [CrossRef] [PubMed]
  138. Tono, T.; Kiyomizu, K.; Matsuda, K.; Komune, S.; Usami, S.; Abe, S.; Shinkawa, H. Different Clinical Characteristics of Aminoglycoside-Induced Profound Deafness with and without the 1555 A→G Mitochondrial Mutation. ORL J. Oto-Rhino-Laryngol. Relat. Spec. 2001, 63, 25–30. [Google Scholar] [CrossRef] [PubMed]
  139. Dowlati, M.A.; Derakhshandeh-Peykar, P.; Houshmand, M.; Farhadi, M.; Shojaei, A.; Fallah, M.; Mohammadi, E.; Tajdini, A.; Arastoo, S.; Tavakkoly-Bazzaz, J. Novel Nucleotide Changes in Mutational Analysis of Mitochondrial 12SrRNA Gene in Patients with Nonsyndromic and Aminoglycoside-Induced Hearing Loss. Mol. Biol. Rep. 2013, 40, 2689–2695. [Google Scholar] [CrossRef] [PubMed]
  140. Granger, D.N.; Kvietys, P.R. Reperfusion Injury and Reactive Oxygen Species: The Evolution of a Concept. Redox Biol. 2015, 6, 524–551. [Google Scholar] [CrossRef] [PubMed]
  141. Crabtree, M.J.; Hale, A.B.; Channon, K.M. Dihydrofolate Reductase Protects Endothelial Nitric Oxide Synthase from Uncoupling in Tetrahydrobiopterin Deficiency. Free Radic. Biol. Med. 2011, 50, 1639–1646. [Google Scholar] [CrossRef]
  142. Rasola, A.; Bernardi, P. The Mitochondrial Permeability Transition Pore and Its Involvement in Cell Death and in Disease Pathogenesis. Apoptosis 2007, 12, 815–833. [Google Scholar] [CrossRef]
  143. Yu, N.; Wang, S.; Wang, P.; Li, Y.; Li, S.; Wang, L.; Chen, H.; Wang, Y. The Calcium Uniporter Regulates the Permeability Transition Pore in Isolated Cortical Mitochondria. Neural Regen. Res. 2012, 7, 109–113. [Google Scholar] [CrossRef]
  144. Moens, A.L.; Claeys, M.J.; Timmermans, J.P.; Vrints, C.J. Myocardial Ischemia/Reperfusion-Injury, a Clinical View on a Complex Pathophysiological Process. Int. J. Cardiol. 2005, 100, 179–190. [Google Scholar] [CrossRef]
  145. Shuvy, M.; Atar, D.; Gabriel Steg, P.; Halvorsen, S.; Jolly, S.; Yusuf, S.; Lotan, C. Oxygen Therapy in Acute Coronary Syndrome: Are the Benefits Worth the Risk? Eur. Heart J. 2013, 34, 1630–1635. [Google Scholar] [CrossRef]
  146. Kontos, H.A.; Wei, E.P. Hydroxyl Radical-Dependent Inactivation of Guanylate Cyclase in Cerebral Arterioles by Methylene Blue and by LY83583. Stroke 1993, 24, 427–434. [Google Scholar] [CrossRef]
  147. Morizane, I.; Hakuba, N.; Hyodo, J.; Shimizu, Y.; Fujita, K.; Yoshida, T.; Gyo, K. Ischemic Damage Increases Nitric Oxide Production via Inducible Nitric Oxide Synthase in the Cochlea. Neurosci. Lett. 2005, 391, 62–67. [Google Scholar] [CrossRef]
  148. Ogawa, H.; Okada, M.; Shudou, M.; Gyo, K.; Hato, N. Prevention of Ischemia-Induced Hearing Loss by Intravenous Administration of Hydrogen-Rich Saline in Gerbil. Neurosci. Lett. 2018, 665, 195–199. [Google Scholar] [CrossRef]
  149. Ackah, S.E.H.; Juhn, S.K.; Huang, T.C.; Wiedmann, T.S. A Combination Antioxidant Therapy Prevents Age-Related Hearing Loss in C57BL/6 Mice. Otolaryngol. Head Neck Surg. 2010, 143, 429–434. [Google Scholar] [CrossRef]
  150. Kishimoto-Urata, M.; Urata, S.; Fujimoto, C.; Yamasoba, T. Role of Oxidative Stress and Antioxidants in Acquired Inner Ear Disorders. Antioxidants 2022, 11, 1469. [Google Scholar] [CrossRef]
  151. Husain, K.; Whitworth, C.; Somani, S.M.; Rybak, L.P. Partial Protection by Lipoic Acid Against Carboplantin-Induced Ototoxicity in Rats. Biomed. Environ. Sci. 2005, 18, 198–206. [Google Scholar] [PubMed]
  152. Aabdallah, D.M.; Eid, N.I. Possible Neuroprotective Effects of Lecithin and Alpha-Tocopherol Alone or in Combination against Ischemia/Reperfusion Insult in Rat Brain. J. Biochem. Mol. Toxicol. 2004, 18, 273–278. [Google Scholar] [CrossRef] [PubMed]
  153. Joachims, H.Z.; Segal, J.; Golz, A.; Netzer, A.; Goldenberg, D. Antioxidants in Treatment of Idiopathic Sudden Hearing Loss. Otol. Neurotol. 2003, 24, 572–575. [Google Scholar] [CrossRef]
  154. Brown, B.G.; Zhao, X.Q.; Chait, A.; Fisher, L.D.; Cheung, M.C.; Morse, J.S.; Dowdy, A.A.; Marino, E.K.; Bolson, E.L.; Alaupovic, P.; et al. Simvastatin and Niacin, Antioxidant Vitamins, or the Combination for the Prevention of Coronary Disease. N. Engl. J. Med. 2001, 345, 1583–1592. [Google Scholar] [CrossRef]
  155. Bielefeld, E.C.; Kopke, R.D.; Jackson, R.L.; Coleman, J.K.; Liu, J.; Henderson, D. Noise Protection with N-Acetyl-l-Cysteine (NAC) Using a Variety of Noise Exposures, NAC Doses, and Routes of Administration. Acta Otolaryngol. 2007, 127, 914–919. [Google Scholar] [CrossRef]
  156. Coleman, J.; Huang, X.; Liu, J.; Kopke, R.; Jackson, R. Dosing Study on the Effectiveness of Salicylate/N-Acetylcysteine for Prevention of Noise-Induced Hearing Loss. Noise Health 2010, 12, 159–165. [Google Scholar] [CrossRef]
  157. Clifford, R.E.; Coleman, J.K.; Balough, B.J.; Liu, J.; Kopke, R.D.; Jackson, R.L. Low-Dose D-methionine and N-acetyl-L-cysteine for Protection from Permanent Noise-Induced Hearing Loss in Chinchillas. Otolaryngol. Head Neck Surg. 2011, 145, 999–1006. [Google Scholar] [CrossRef]
  158. Fetoni, A.R.; Ralli, M.; Sergi, B.; Parrilla, C.; Troiani, D.; Paludetti, G. Protective Effects of N-Acetylcysteine on Noise-Induced Hearing Loss in Guinea Pigs. Acta Otorhinolaryngol. Ital. 2009, 29, 70–75. [Google Scholar]
  159. Lorito, G.; Giordano, P.; Petruccelli, J.; Martini, A.; Hatzopoulos, S. Different Strategies in Treating Noiseinduced Hearing Loss with N-Acetylcysteine. Med. Sci. Monit. 2008, 14, BR159–BR164. [Google Scholar]
  160. Samson, J.; Wiktorek-Smagur, A.; Politanski, P.; Rajkowska, E.; Pawlaczyk-Luszczynska, M.; Dudarewicz, A.; Sha, S.H.; Schacht, J.; Sliwinska-Kowalska, M. Noise-Induced Time-Dependent Changes in Oxidative Stress in the Mouse Cochlea and Attenuation by D-methionine. Neuroscience 2008, 152, 146–150. [Google Scholar] [CrossRef]
  161. Kundu, S.; Munjal, C.; Tyagi, N.; Sen, U.; Tyagi, A.C.; Tyagi, S.C. Folic Acid Improves Inner Ear Vascularization in Hyperhomocysteinemic Mice. Hear. Res. 2012, 284, 42–51. [Google Scholar] [CrossRef] [PubMed]
  162. Hou, F.; Wang, S.; Zhai, S.; Hu, Y.; Yang, W.; He, L. Effects of Alpha-Tocopherol on Noise-Induced Hearing Loss in Guinea Pigs. Hear. Res. 2003, 179, 1–8. [Google Scholar] [CrossRef] [PubMed]
  163. Scholik, A.R.; Lee, U.S.; Chow, C.K.; Yan, H.Y. Dietary Vitamin E Protects the Fathead Minnow, Pimephales promelas, Against Noise Exposure. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2004, 137, 313–323. [Google Scholar] [CrossRef]
  164. Kalkanis, J.G.; Whitworth, C.; Rybak, L.P. Vitamin E Reduces Cisplatin Ototoxicity. Laryngoscope 2004, 114, 538–542. [Google Scholar] [CrossRef]
  165. Teranishi, M.A.; Nakashima, T. Effects of Trolox, Locally Applied on Round Windows, on Cisplatin-Induced Ototoxicity in Guinea Pigs. Int. J. Pediatr. Otorhinolaryngol. 2003, 67, 133–139. [Google Scholar] [CrossRef]
  166. Sergi, B.; Fetoni, A.R.; Ferraresi, A.; Troiani, D.; Azzena, G.B.; Paludetti, G.; Maurizi, M. The Role of Antioxidants in Protection from Ototoxic Drugs. Acta Oto-Laryngol. Suppl. 2004, 552, 42–45. [Google Scholar] [CrossRef]
  167. Fetoni, A.R.; Sergi, B.; Ferraresi, A.; Paludetti, G.; Troiani, D. Alpha-Tocopherol Protective Effects on Gentamicin Ototoxicity: An Experimental Study. Int. J. Audiol. 2004, 43, 166–171. [Google Scholar] [CrossRef]
  168. Sato, K. Pharmacokinetics of Coenzyme Q10 in Recovery of Acute Sensorineural Hearing Loss Due to Hypoxia. Acta Otolaryngol. Suppl. 1988, 458, 95–102. [Google Scholar] [CrossRef]
  169. Sergi, B.; Fetoni, A.R.; Paludetti, G.; Ferraresi, A.; Navarra, P.; Mordente, A.; Troiani, D. Protective Properties of Idebenone in Noise-Induced Hearing Loss in the Guinea Pig. NeuroReport 2006, 17, 857–861. [Google Scholar] [CrossRef]
  170. Fetoni, A.R.; Piacentini, R.; Fiorita, A.; Paludetti, G.; Troiani, D. Water-Soluble Coenzyme Q10 Formulation (Q-ter) Promotes Outer Hair Cell Survival in a Guinea Pig Model of Noise Induced Hearing Loss (NIHL). Brain Res. 2009, 1257, 108–116. [Google Scholar] [CrossRef]
  171. Le Prell, C.G.; Hughes, L.F.; Miller, J.M. Free Radical Scavengers Vitamins A, C, and E plus Magnesium Reduce Noise Trauma. Free Radic. Biol. Med. 2007, 42, 1454–1463. [Google Scholar] [CrossRef]
  172. Sebastian, C.; Mostoslavsky, R. SIRT3 in Calorie Restriction: Can You Hear Me Now? Cell 2010, 143, 667–668. [Google Scholar] [CrossRef]
  173. Guarente, L. Mitochondria--A Nexus for Aging, Calorie Restriction, and Sirtuins? Cell 2008, 132, 171–176. [Google Scholar] [CrossRef]
  174. Someya, S.; Yu, W.; Hallows, W.C.; Xu, J.; Vann, J.M.; Leeuwenburgh, C.; Tanokura, M.; Denu, J.M.; Prolla, T.A. Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss Under Caloric Restriction. Cell 2010, 143, 802–812. [Google Scholar] [CrossRef]
  175. Curhan, S.G.; Stankovic, K.M.; Eavey, R.D.; Wang, M.; Stampfer, M.J.; Curhan, G.C. Carotenoids, Vitamin A, Vitamin C, Vitamin E, and Folate and Risk of Self-Reported Hearing Loss in Women. Am. J. Clin. Nutr. 2015, 102, 1167–1175. [Google Scholar] [CrossRef]
  176. Shargorodsky, J.; Curhan, S.G.; Eavey, R.; Curhan, G.C. A Prospective Study of Vitamin Intake and the Risk of Hearing Loss in Men. Otolaryngol. Head Neck Surg. 2010, 142, 231–236. [Google Scholar] [CrossRef]
  177. Gopinath, B.; Flood, V.M.; McMahon, C.M.; Burlutsky, G.; Spankovich, C.; Hood, L.J.; Mitchell, P. Dietary Antioxidant Intake Is Associated with the Prevalence but Not Incidence of Age-Related Hearing Loss. J. Nutr. Health Aging 2011, 15, 896–900. [Google Scholar] [CrossRef]
  178. Kramer, S.; Dreisbach, L.; Lockwood, J.; Baldwin, K.; Kopke, R.; Scranton, S.; O’Leary, M. Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music. J. Am. Acad. Audiol. 2006, 17, 265–278. [Google Scholar] [CrossRef]
  179. Feldman, L.; Efrati, S.; Eviatar, E.; Abramsohn, R.; Yarovoy, I.; Gersch, E.; Averbukh, Z.; Weissgarten, J. Gentami-cin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine. Kidney Int. 2007, 72, 359–363. [Google Scholar] [CrossRef]
  180. Kharkheli, E.; Kevanishvili, Z.; Maglakelidze, T.; Davitashvili, O.; Schacht, J. Does vitamin E prevent gentami-cin-induced ototoxicity? Georgian Med. News. 2007, 146, 14–17. [Google Scholar]
  181. Yıldırım, M.; Inançlı, H.M.; Samancı, B.; Oktay, M.F.; Enöz, M.; Topçu, I. Preventing cisplatin induced ototoxicity by N-acetylcysteine and salicylate. Kulak Burun Bogaz Ihtis Derg. 2010, 20, 173–183. [Google Scholar]
  182. Lin, C.Y.; Wu, J.L.; Shih, T.S.; Tsai, P.J.; Sun, Y.M.; Ma, M.C.; Guo, Y.L. N-Acetyl-cysteine against noise-induced temporary threshold shift in male workers. Hear. Res. 2010, 269, 42–47. [Google Scholar] [CrossRef]
  183. Tokgoz, B.; Ucar, C.; Kocyigit, I.; Somdas, M.; Unal, A.; Vural, A.; Sipahioglu, M.; Oymak, O.; Utas, C. Protective effect of N-acetylcysteine from drug-induced ototoxicity in uraemic patients with CAPD peritonitis. Nephrol. Dial. Transplant. 2011, 26, 4073–4078. [Google Scholar] [CrossRef] [PubMed]
  184. Yang, C.H.; Ko, M.T.; Peng, J.P.; Hwang, C.F. Zinc in the treatment of idiopathic sudden sensorineural hearing loss. Laryngoscope 2011, 121, 617–621. [Google Scholar] [CrossRef] [PubMed]
  185. Hoffer, M.E.; Balaban, C.; Slade, M.D.; Tsao, J.W.; Hoffer, B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: A double-blind, placebo controlled study. PLoS ONE 2013, 8, e54163. [Google Scholar] [CrossRef] [PubMed]
  186. Doosti, A.; Lotfi, Y.; Moossavi, A.; Bakhshi, E.; Talasaz, A.H.; Hoorzad, A. Comparison of the effects of N-acetyl-cysteine and ginseng in prevention of noise induced hearing loss in male textile workers. Noise Health 2014, 16, 223–227. [Google Scholar] [CrossRef] [PubMed]
  187. Kang, H.S.; Park, J.J.; Ahn, S.K.; Hur, D.G.; Kim, H.Y. Effect of high dose intravenous vitamin C on idiopathic sudden sensorineural hearing loss: A prospective single-blind randomized controlled trial. Eur. Arch. Otorhinolaryngol. 2013, 270, 2631–2636. [Google Scholar] [CrossRef]
  188. Kopke, R.; Slade, M.D.; Jackson, R.; Hammill, T.; Fausti, S.; Lonsbury-Martin, B.; Sanderson, A.; Dreisbach, L.; Rabinowitz, P.; Torre, P., 3rd; et al. Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: A randomized clinical trial. Hear. Res. 2015, 323, 40–50. [Google Scholar] [CrossRef] [PubMed]
  189. Villani, V.; Zucchella, C.; Cristalli, G.; Galiè, E.; Bianco, F.; Giannarelli, D.; Carpano, S.; Spriano, G.; Pace, A. Vitamin E neuroprotection against cisplatin ototoxicity: Preliminary results from a randomized, placebo-controlled trial. Head Neck 2016, 38 (Suppl. S1), E2118–E2121. [Google Scholar] [CrossRef] [PubMed]
  190. Freyer, D.R.; Chen, L.; Krailo, M.D.; Knight, K.; Villaluna, D.; Bliss, B.; Pollock, B.H.; Ramdas, J.; Lange, B.; Van Hoff, D.; et al. Effects of sodium thiosulfate versus observation on devel-opment of cisplatin-induced hearing loss in children with cancer (ACCL0431): A multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017, 18, 63–74. [Google Scholar] [CrossRef] [PubMed]
  191. Kil, J.; Lobarinas, E.; Spankovich, C.; Griffiths, S.K.; Antonelli, P.J.; Lynch, E.D.; Le Prell, C.G. Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2017, 390, 969–979. [Google Scholar] [CrossRef]
  192. Brock, P.R.; Maibach, R.; Childs, M.; Rajput, K.; Roebuck, D.; Sullivan, M.J.; Laithier, V.; Ronghe, M.; Dall’Igna, P.; Hiyama, E.; et al. Sodium Thiosulfate for Protection from Cispla-tin-Induced Hearing Loss. N. Engl. J. Med. 2018, 378, 2376–2385. [Google Scholar] [CrossRef]
  193. Rolland, V.; Meyer, F.; Guitton, M.J.; Bussières, R.; Philippon, D.; Bairati, I.; Leclerc, M.; Côté, M. A randomized controlled trial to test the efficacy of trans-tympanic injections of a sodium thiosulfate gel to prevent cisplatin-induced oto-toxicity in patients with head and neck cancer. J. Otolaryngol. Head Neck Surg. 2019, 48, 4. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Summary figure of mitochondrial oxidative stress in relation to hearing loss. When the balance between the production and elimination of ROS is disrupted, cellular physiology is affected. Mitochondria play an important role in ROS production. Excessive levels of ROS, caused by external factors such as noise or ototoxic drugs, compromise the antioxidant defenses of hair cells, induce apoptosis, and cause inflammation, resulting in permanent cochlear degeneration.
Figure 1. Summary figure of mitochondrial oxidative stress in relation to hearing loss. When the balance between the production and elimination of ROS is disrupted, cellular physiology is affected. Mitochondria play an important role in ROS production. Excessive levels of ROS, caused by external factors such as noise or ototoxic drugs, compromise the antioxidant defenses of hair cells, induce apoptosis, and cause inflammation, resulting in permanent cochlear degeneration.
Ijms 25 04146 g001
Table 1. Summary of randomized clinical trials on antioxidants for the treatment of hearing loss.
Table 1. Summary of randomized clinical trials on antioxidants for the treatment of hearing loss.
Summary of RCTs of Antioxidants on Hearing Loss in Humans
AuthorYearAntioxidantsType of Hearing LossObjectivesSample Size
(Patients vs. Control)
Main Findings
Kramer S et al. [178]2006N-acetylcysteineLoud noiseNormal hearing participants31
(N/A)
No statistically significant differences
L Feldman et al. [179]2007N-acetylcysteineGentamicin-induced ototoxicityHemodialysis patients40
(20/20)
Significantly more patients exhibiting ototoxicity in the control group
E Kharkheli et al. [180]2007Vitamin EGentamicin-induced ototoxicityAcute pulmonary infections52
(23/29)
No statistically significant differences
Yıldırım M et al. [181]2010Salicylate/N-acetylcysteineCisplatin-induced ototoxicitySolid organ tumors 54
(18/18/18)
No difference detected between N-acetylcysteine or salicylate
Lin CY et al. [182]2010N-acetylcysteineNoise-induced temporary threshold shiftMale workers53
(25/28)
NAC significantly reduced TTS (p = 0.03)
Effects were more prominent both GSTM1-null and GSTT1-null genotypes.
Tokgoz B et al. [183]2011N-acetylcysteineOtotoxicity drug-induced
(Aminoglycosides and vancomycin)
Continuous ambulatory peritoneal dialysis treatment60
(30/30)
Patients taking NAC had better hearing function test results 4 weeks after the treatment (p < 0.05)
Yang CH et al. [184]2011ZincIdiopathic sudden sensorineural hearing lossSSNHL patients66
(33/33)
A significantly larger hearing gain, an increased percentage of recovery, and an increased rate of successful recovery
Hoffer ME et al. [185]2013N-acetylcysteineBlast exposureActive duty service members81
(41/40)
In a seven day symptom resolution rate of 86% as compared to 11%
Doosti A et al. [186]2014N-Acetylcysteine/GinsengNoise-inducedTextile workers48
(16/16/16)
Reduced noise-induced TTS for NAC and ginseng groups at 4, 6 and 16 kHz (p < 0.001)
Kang HS et al. [187]2014Vitamin CIdiopathic sudden sensorineural hearing lossSSNHL patients67
(35/32)
HDVC group showed significantly greater complete and partial recovery
improvement (p = 0.035)
Kopke R et al. [188]2015N-acetylcysteineMilitary noise during weapons trainingHealthy Marine Corps recruit volunteers566
(277/289)
No significant differences were found for the primary outcome
Villani V et al. [189]2016Vitamin ECisplatin-induced ototoxicitySolid malignancies23
(13/10)
At 1 month, a significant hearing loss at 2k and 8k HZ k was detected
in placebo group
Freyer DR et al. [190]2017Sodium thiosulfateCisplatin-induced Aged 1–18 years with newly
diagnosed cancer
125
(61/64)
The likelihood of hearing loss was significantly lower in the sodium
thiosulfate group (p = 0.0036)
Kil J et al. [191]2017EbselenCalibrated sound challengeHealthy adults aged 18–31 years83
(22/20/21/20)
Mean TTS at 4 kHz was in the 400 mg ebselen group representing a
significant reduction of 68% (p = 0.0025)
Brock PR et al. [192]2018Sodium thiosulfateCisplatin-induced ototoxicityHepatoblastoma patients109
(57/52)
48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate
group (p = 0.002)
Rolland V et al. [193]2019Sodium thiosulfateCisplatin-induced ototoxicityStage III or IV squamous cell
carcinoma
13
(N/A)
Not statistically nor clinically significant differences
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Teraoka, M.; Hato, N.; Inufusa, H.; You, F. Role of Oxidative Stress in Sensorineural Hearing Loss. Int. J. Mol. Sci. 2024, 25, 4146. https://doi.org/10.3390/ijms25084146

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Teraoka M, Hato N, Inufusa H, You F. Role of Oxidative Stress in Sensorineural Hearing Loss. International Journal of Molecular Sciences. 2024; 25(8):4146. https://doi.org/10.3390/ijms25084146

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Teraoka, Masato, Naohito Hato, Haruhiko Inufusa, and Fukka You. 2024. "Role of Oxidative Stress in Sensorineural Hearing Loss" International Journal of Molecular Sciences 25, no. 8: 4146. https://doi.org/10.3390/ijms25084146

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Teraoka, M., Hato, N., Inufusa, H., & You, F. (2024). Role of Oxidative Stress in Sensorineural Hearing Loss. International Journal of Molecular Sciences, 25(8), 4146. https://doi.org/10.3390/ijms25084146

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