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Auditory research involving anti

oxidantsIlaaf Darrat, Nadir Ahmad, Kevin Seidman and Michael D. Seidman

Purpose of review

The role of antioxidants in the management of hearing loss

has generated considerable interest over the past several

years. Research efforts in this field have yielded many new

insights into the molecular and cellular nature of several

types of hearing impairment, including age-related, noise-

induced, and drug-induced hearing loss. The objective of

this paper is to highlight some of the important studies

published over the past several years that have further

contributed to our understanding of the mechanism of

antioxidants in attenuating hearing loss.

Recent findings

There is compelling evidence to suggest that antioxidant

therapy is beneficial in attenuating, improving, or reversing

the effects of several types of acquired hearing loss. Cellular

and subcellular changes resulting from these types of

hearing impairment are remarkably similar and seem to have

a common putative mechanism of oxidative stress and

damage. Recent studies have lent further credibility to the

notion that antioxidant therapy can be of considerable

benefit in the treatment of hearing loss. The increasing body

of literature pertaining to human studies will shed further

light into this fascinating area of research.

Summary

This review elucidates the role of antioxidants in hearing

loss and illustrates the continued evolution of research

efforts in this field.

Keywords

antioxidants, drug-induced hearing loss, noise-induced

hearing loss, NIHL, presbyacusis, reactive oxygen species

Curr Opin Otolaryngol Head Neck Surg 15:358–363. � 2007 Lippincott Williams &Wilkins.

Department of Otolaryngology, Head and Neck Surgery, Henry Ford Hospital,Detroit, Michigan, USA

Correspondence to Michael D. Seidman, MD, FACS, Department ofOtolaryngology-Head and Neck Surgery, Director, Division of Otologic/Neurotologic Surgery, Henry Ford Hospital, Director of Complementary/IntegrativeMedicine, 6777 West Maple Road, West Bloomfield, MI 48323, USATel: +1 248 661 7211; fax: +1 248 661 6456; e-mail: mseidma1@hfhs.org

Current Opinion in Otolaryngology & Head and Neck Surgery 2007,15:358–363

Abbreviations

ALCAR a

opyrigh

358

cetyl-L-carnitine

DPOAE d istortion product otoacoustic emission MHA m embrane hypothesis of aging NAC N -acetylcysteine NIHL n oise-induced hearing loss ROS re active oxygen species SRG s teamed roots of Rehmannia glutinosa STS s odium thiosulphate

� 2007 Lippincott Williams & Wilkins1068-9508

t © Lippincott Williams & Wilkins. Unautho

IntroductionThe role of antioxidants in attenuating hearing loss has

been the subject of much interest, scrutiny, criticism, and

controversy over the past several years. The plethora of

research studies in this field attests to the impact that

antioxidants have had on scientific thought and our

society overall. Over the past year, several studies have

been published that largely support the role of antiox-

idants in reversing or attenuating the deleterious effects

of reactive oxygen species (ROS). This trend has been

noted in earlier studies and has been the impetus for

continuing research efforts in this field.

An increase in reactive oxygen species (ROS) production

is postulated to play an important role in age-related,

noise-induced, and drug-induced hearing loss. ROS con-

tain an unpaired number of electrons, rendering them

chemically reactive and toxic to cellular and subcellular

structures. ROS have been implicated in the pathophy-

siologic processes of more than 100 medical conditions

[1]. They are generated in vivo as a byproduct of mito-

chondrial respiration, and are also produced via autoox-

idation of chemical and biological molecules. ROS

are also environmental contaminants and can be formed

from ionizing and ultraviolet radiation. The most com-

mon ROS are superoxide anion (O2�), hydroxyl radical

(OH�), hypochlorite (OCl�), and nitric oxide (NO�).

ROS are converted to nonreactive molecules by endogen-

ous cellular enzymes, such as copper/zinc superoxide

dismutase (SOD1), manganese superoxide dismutase

(SOD2), catalase, and peroxidase. Additionally, the admin-

istration of exogenous antioxidants, such as a-lipoic acid,

acetyl-L-carnitine (ALCAR), N-acetylcysteine (NAC),

vitamins E and C, and phytochemicals, also results in

scavenging of ROS. The medical literature has overwhel-

mingly supported the protective effects of antioxidants

and ROS scavengers on age-related, noise-induced, and

drug-induced hearing loss. Several studies and review

articles from the senior author’s laboratory have helped

to elucidate some of the molecular events leading to these

various types of acquired hearing loss, as well as to identify

specific antioxidants that have significant beneficial effects

on hearing loss [2–9].

Antioxidants in age-related hearing lossPresbyacusis is the progressive, high frequency, sensor-

ineural hearing loss that occurs with advancing age. The

accumulation of ROS is strongly implicated in the aging

process and is regarded as an important deleterious

event in the genesis of presbyacusis [10]. The persistent

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Auditory research involving antioxidants Darrat et al. 359

interaction of ROS with cellular and subcellular

(i.e. mitochondrial) structures ultimately leads to tissue

damage and cell death. The National Institutes of

Health has estimated that approximately 30–35% of

adults between the ages of 65 and 75 years have some

degree of hearing loss [11]. Furthermore, approximately

40–50% of people aged 75 years and older have hearing

loss that can impair communication.

Numerous hypotheses have been advocated to explain

the mechanisms of the aging process. These can be

broadly grouped into two categories: those that impli-

cate deterministic, or ‘programmed’, alterations in gene

expression or gene structure; and those that implicate

a variety of stochastic or ‘random’ alterations in the

structure and function of macromolecules, cells and

organ systems. The corresponding author’s laboratory

and others have also provided compelling evidence that

diseases associated with the aging process result from the

accumulation of ROS. ROS directly damages subcellular

structures, such as mitochondrial DNA (mtDNA), creating

deletions and mutations, subsequently producing bio-

energetically deficient cells. This cascade of events leads

to senescence, cell death, and hearing loss. Senescence is

the progressive accumulation of metabolic and physio-

logic derangements, which increases susceptibility to

disease. Several theories have been proposed to explain

the phenomenon of senescence. The most convincing

theories are the telomerase theory of aging, the dysdiffer-

entiation hypothesis of aging, and the membrane

hypothesis of aging (MHA), also referred to as the

mitochondrial clock theory of aging.

In the telomerase theory of aging, a reduction in telomere

length occurs over time. The end of a chromosome is

composed of a structure called the telosome, the tip of

which is the telomere. Reduction in the length of the

telomere and alterations in its chromatin assembly may

account for the instability that occurs during senescence

[12]. It has been suggested that the balance between

telomere shortening and telomerase activity may underlie

various cellular aging processes.

In the dysdifferentiation theory, aging occurs on a con-

tinuum of programmed differentiation leading to either a

cessation of normal gene activity or a systematic acti-

vation of genes whose effects are deleterious to cellular

function.

The MHA suggests that aging is related to a decreased

effectiveness of cellular protective and reparative mech-

anisms, yielding biochemical and metabolic errors that

progressively accumulate, resulting in eventual cell death

[13]. Furthermore, the MHA postulates that cellular

senescence is attributable to the cross-linking action

of ROS or radicals within the cellular membrane.

opyright © Lippincott Williams & Wilkins. Unauth

Additionally, these ROS result in lipid peroxidation,

polysaccharide depolymerization, nucleic acid disrup-

tion, and oxidation of sulfhydryl groups, leading to

enzyme inactivation [14]. Hence, the MHA suggests that

ROS induced cell membrane structural damage is the

primary mediating event in cellular aging [15,16]. It is

plausible that various aspects of these theories occur in

concert and serve to better explain the aging process.

For example, ROS generation leads to genetic and

cellular alterations resulting in cellular dysfunction,

and consequently to senescence.

Significant progress has been made to identify the mol-

ecular mechanisms of age-related hearing loss. This in

turn has led to research on methods of mitigating the

adverse effects on the auditory system. Understanding of

the relevant mechanisms of aging provides a potential

roadmap for interventional therapeutic strategies to coun-

teract the processes of aging. There is increasing evi-

dence suggesting that ROS have a putative role in the

damage associated with cochlear ischemia, noise trauma,

aging, presbyacusis, and ototoxicity.

The focus of the corresponding author’s laboratory is to

elucidate the mechanisms of aging, specifically the role

that ROS plays in this process. The aging process partly

occurs due to oxidative stress, resulting in increased

mitochondrial DNA mutations, and a concomitant

reduction in mitochondrial function. These changes

ultimately lead to cellular and subcellular dysfunction,

which likely manifests in the inner ear milieu as a

significant decrease in auditory sensitivity. The gener-

ation of these ROS is partly responsible for the

reduction in the mitochondrial membrane potential

and the loss of cochlear hair cells, with an attendant

increase in the auditory threshold. These deleterious

effects of aging can be slowed and in some situations

even reversed through strategies that affect the bio-

energetic properties of cells. In 2000, a study published

from our laboratory demonstrated significant protec-

tive effect in auditory thresholds in subjects either

treated with specific antioxidants or caloric restriction.

The results of this 5-year series of experiments

represented the first prospective randomized trial

designed to investigate the effect of antioxidants, nutri-

tional supplementation and dietary restriction on hearing

loss specifically and aging in general. This study and

earlier ones were the first to propose that the mechanism

involving the generation of ROS and resultant damage to

mitochondria may be responsible for presbyacusis

[2,3,5]. The findings from these experiments demon-

strated that dietary restriction and specific nutrient

supplementation reduce the progression of age-related

hearing loss [5]. This beneficial effect was thought to

likely represent a reduction in oxidative stress through

antioxidant therapy.

orized reproduction of this article is prohibited.

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360 Hearing science

In the past year, several studies have corroborated the

evidence accumulated from previous years and those

obtained from our laboratory. In a recent article by de

Rivera et al. [17�], the effect of blueberry phytochemical,

an antioxidant, on the speed of temporal processing in

primary auditory cortex aged rats was investigated. This

study showed that the frequency modulated sweep in the

aged rats that had been fed a blueberry-enriched diet for

8 weeks was faster than aged rats that had been feed corn

pellet or normal rat chow pellets. Furthermore, the aged

rats that were fed the blueberry-enriched diet had a faster

frequency modulated sweep than young rats. This was

the first study to investigate the effects of blueberry

phytochemicals on sensory processing. Le and Keithley

[18�] investigated the effects of an antioxidant-rich diet in

beagle dogs on age-related cochlear structural changes.

They found that the dogs that were fed a diet rich in

vitamin E, L-carnitine, DL-a-lipoic acid, and vitamin C

in the last 3 years of their lives exhibited a greater

neuronal density in the apical turn of the spiral ganglion

versus an age-matched control group. When these anti-

oxidant-enriched dogs were compared with a younger

group of dogs, there was no difference in the neuronal

density between the two. In addition, when comparing

the stria vascularis thickness in the antioxidant-enriched

aged dogs versus the age-matched control group, there

was a larger amount of neuronal degeneration at the basal

and apical ends of the cochlea in the age-matched control

group. The stria vascularis is rich in mitochondria.

Exposure to ROS results in degradation of the mitochon-

dria, thus contributing to age-related ultrastructural

changes in the cochlea. Auditory thresholds were not

obtained during this study, however, thus conclusions

about resultant hearing differences would be speculative.

Nevertheless, these types of studies offer significant

promise for the treatment of presbyacusis. Research

efforts need to be directed to performing prospective

randomized studies in humans to more convincingly

demonstrate the beneficial and powerful effect of anti-

oxidants on age-related hearing loss. These studies, how-

ever, provide encouraging evidence that antioxidants

may slow down, reverse or improve the process of age-

related hearing loss. The research on antioxidants and

their role in attenuating or reversing the effects of age-

related hearing loss is compelling and overwhelmingly

positive. Our contention is a diet rich in certain specific

antioxidants should be offered to all patients experien-

cing age-related hearing loss.

Antioxidants in noise-induced hearing lossNoise-induced hearing loss (NIHL) is a type of high-

frequency sensorineural hearing loss, often with a classic

notch at 4000 Hz. It is a preventable cause of hearing loss

caused by excessive exposure to either acute or chronic

acoustic trauma. Though NIHL is usually associated with

occupational exposure such as in the automotive industry

opyright © Lippincott Williams & Wilkins. Unautho

and the military, it also occurs as a result of recreational

pursuit exposure, such as using personal listening

devices. Acoustic trauma can be tremendous enough to

cause mechanical disruption of the cochlea resulting in

immediate, permanent hearing loss. Most clinical

scenarios, however, are due to a gradual hearing loss,

which results from cumulative oxidative metabolic stress

and damage. Considerable research [19��] has been

aimed at investigating antioxidants to treat or prevent

the onset or progression of NIHL. The senior author has

studied the effects of resveratrol, a phytoalexin and

nutritional supplement found in the skin of red grapes,

on acoustic trauma. In a study published in 2003, resver-

atrol supplementation was noted to reduce threshold

shifts in young rats exposed to significant acoustic trauma

(105 dB over a range of 4500–9000 Hz, for 24 h) compared

to a similar group of rats supplemented only with normal

saline [20].

With massive noise stimulation, an excessive amount of

glutamate, a neurotransmitter at the junction of the inner

hair cells and afferent neuron in the peripheral auditory

system, is released resulting in ionic influx and massive

entry of water and extracellular calcium into the afferent

neurons, causing cell death and noise induced hearing

loss [21,22]. Duan et al. [23�] investigated the protective

effect of caroverine, an antioxidant and an antagonist

of two glutamate receptors, against acoustic trauma in

rats. The rats were divided into two groups, one that was

pretreated with administration of subcutaneous carover-

ine for 72 h, and a second group given subcutaneous

saline. After 48 h, each group was exposed to impulse

noise at 160 dB. The study revealed that prior to

impulse noise insult, subcutaneously administered

caroverine decreased impulse noise-induced hearing

loss in rats. An antioxidant that has been extensively

studied in relation to NIHL is NAC. NAC stimulates the

production of the major cellular antioxidant, glutathione

in hair cells [24], acts as a free radical scavenger, and

inhibits cell death pathway enzymes [25–28]. Coleman

et al. [29��] investigated the protective effect of NAC 1, 4,

and 12 h after NIHL in chinchillas. The animals were

divided into three groups: those administered a saline

control, those supplemented with NAC, and those given

ALCAR (a mitochondrial bio-energy maintenance and

integrity compound). The animals were first exposed to

6 h of 105 dB sound-pressure level octave band noise

centered at 4000 Hz. One hour after noise exposure,

the greatest decrease in hearing loss was noted in the

NAC and ALCAR supplemented groups. There was no

improvement in hearing, however, when NAC and

ALCAR were administrated 12 h after noise exposure.

To determine the effect of NAC on NIHL in humans,

as the other studies described herein have been in

animals, Kramer et al. [30�] performed a randomized,

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Auditory research involving antioxidants Darrat et al. 361

double-blinded, placebo-controlled study. Distortion

product otoacoustic emission (DPOAE) measurements

were performed on the participants before and 2 h after

exposure to live music at a nightclub. The participants

were either given a 900 mg tablet of NAC or a placebo

30 min before noise exposure. No statistical significance

was seen in either group in DPOAE measurements.

Though the study did not show a protective benefit of

NAC in humans, it is still believed that taking NAC

before noise exposure is beneficial. A randomized,

double-blinded, placebo controlled study in humans that

investigated the effect of NAC at different doses and

varying time schedules still needs to be performed to

demonstrate a statistically significant protective effect of

NAC in NIHL.

Antioxidants in drug-induced hearing lossPlatinum based chemotherapeutic agents and aminogly-

cosides have been shown to be ototoxic, often resulting in

bilateral, symmetric sensorineural hearing loss. Of the

platinum based agents, cisplatin is more commonly and

classically associated with ototoxicity, though carboplatin

has also been shown to be ototoxic. Coling et al. [31��]

identified three of the five cochlear proteins that are

upregulated and four of the 17 cochlear proteins that

are downregulated with cisplatin treatment causing oto-

toxicity. Cisplatin administration results in ROS gener-

ation, [32] causing an increase in lipid peroxidation of cell

membranes, which results in outer hair cell damage [33].

The effects of cisplatin ototoxicity also manifest in the

organ of Corti, spiral ganglion cells, and the stria vascu-

laris. The damage that is caused to the organ of Corti is

permanent, but the damage to the stria vascularis is

transient. Similarly, aminoglycosides directly damage

the outer hair cell membrane. Though the mechanism

of action is not completely understood, ROS production

has been suggested as a causative factor [34–36].

Sodium thiosulphate (STS), a reactive thiol compound,

has been investigated extensively and found to reduce

ototoxicity caused by cisplatin in mice and guinea pigs

[37–38]. STS acts by binding and inactivating the

platinum-containing DNA alkylating agents, and by act-

ing as a free radical scavenger. This results in otoprotec-

tion from cisplatin and carboplatin [39�]. It has been

shown, however, that co-administration of sodium thio-

sulphate and cisplatin can reduce the antitumor effects of

cisplatin [37]. Neuwelt et al. [39�] investigated carbopla-

tin and ototoxicity in children. The objective of their

study was to determine whether delaying STS adminis-

tration 4 h after carboplatin would be protective in

12 children treated for a brain tumor. Though the data

were not statistically significant, owing to a small sample

size, it was determined that high dose STS was safe in

children. A natural antioxidant that has been found to

opyright © Lippincott Williams & Wilkins. Unauth

resolve inner ear symptoms is the ethanol extract of the

steamed roots of Rehmannia glutinosa Liboschitz (SRG)

[40]. Yu et al. [41�] investigated the dose of SRG that would

prevent cisplatin ototoxicity. HEI-OCI auditory cells were

pretreated with 0, 5, 10, 50 and 100mg/ml of SRG for 1 h,

after which cisplatin was added to each cell culture.

SRG prevented cisplatin-induced lipid peroxidation in a

dose-dependent manner. In addition, it was found that

SRG acts as a free radical scavenger by removing ROS,

more specifically, hydrogen peroxide, hydroxyl radical,

and 1,1-dipheny-2-picrylhydrazyl (DPPH) radicals. To

determine the protective effects of sodium thiosulphate

on gentamicin-induced hearing loss, Hochman et al. [42�]

investigated the effects on C57 mice. There were four

groups: a group receiving intraperitoneal injection of only

gentamicin, a group receiving injection of only sodium

thiosulphate, a group receiving injection of both of gen-

tamicin and sodium thiosulphate, and a group injected

with normal saline. Auditory brainstem response (ABR)

thresholds were recorded at initiation of the study and then

on day 35. Though the results showed a promising trend

towards a protective effect of sodium thiosulphate, it was

not statistically significant.

These studies suggest that antioxidants can protect

against drug-induced hearing loss, though further studies

are needed to clearly advocate the routine prophylactic

and therapeutic use of antioxidants in drug-induced

hearing loss. The platinum based chemotherapeutic

agents and aminoglycosides are widely used and thus

further evidence to clearly support or demonstrate a

positive trend is needed to allow for widespread accep-

tance of antioxidant use with administration of these

potentially deleterious drugs.

ConclusionThe role of antioxidants in the management of age-

related, noise-induced and drug-induced hearing loss

continues to evolve and be elucidated. Studies published

in the last several years have yielded promising results

and are strongly suggestive of a protective role for these

compounds. These studies have been largely limited to

animal models and the research focus clearly needs to

shift to more randomized, placebo-controlled, double-

blinded studies in humans. Nevertheless, results from an

overwhelming majority of studies on antioxidants and

acquired hearing loss demonstrate the beneficial effects

of these compounds at a cellular and subcellular level, as

well as in objective measures of hearing sensitivity, such

as ABR testing. Two recent studies presented at the

Combined Otolaryngology Sections Meeting (COSM)

in San Diego (April 2007) highlight the continued

research efforts in the field of antioxidant therapy. A

study directed by Kopke et al. [43] investigated the role

of oral NAC administration given during weapons train-

ing in the Marine Corps; 566 subjects were enrolled in the

orized reproduction of this article is prohibited.

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362 Hearing science

study, of which 289 were given placebo and 277 given

NAC. The subjects received 900 mg/day of NAC or

placebo for 16 days. Hearing status was evaluated prior

to and 10 days following the 16-day weapons training,

using pure-tone audiometry and DPOAEs. The results

demonstrated a significant effect of NAC in reducing

the significant threshold shift in ears exposed to more

intense acoustic trauma at the dose used. The conclusion

was that oral NAC was safe and effective [43]. Another

study presented by Choi et al. [44] looked at the effec-

tiveness of combinations of antioxidant compounds

in the treatment of acute acoustic trauma. In the study,

three groups of chinchillas (six per group) were exposed

to 105 dB narrow-band noise centered at 4 kHz for 6 h.

These groups were administered different antioxidant

compound combinations and at different doses. The

antioxidants studies were NAC, ALCAR and hydroxyl-

ated a-phenyl-tert-butylnitrone (4-OH-PBN). The

results demonstrated that the chinchillas administered

the two types of drug combinations and at different doses

had their permanent threshold shifts completely elimi-

nated as opposed to the chinchillas given a control carrier

solution [44]. These results support the judicious use of

antioxidants in individualized cases of acquired hearing

loss. The medical practitioners’ understanding of the

literature regarding antioxidant use in hearing loss and

recognition of the risks, benefits and alternatives of this

type of therapy is paramount to appropriate management

and counseling of patients.

References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:� of special interest�� of outstanding interest

Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (p. 377).

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29

��Coleman JK, Kopke RD, Liu J, et al. Pharmacological rescue of noise inducedhearing loss using N-acetylcysteine and acetyl-L-carnitine. Hear Res 2007;226:104–113.

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30

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31

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This paper investigates the protective effect of STS on carboplatin-inducedhearing loss in children.

opyright © Lippincott Williams & Wilkins. Unauth

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41

�Yu HH, Seo SJ, Kim YH, et al. Protective effect of Rehmannia glutinosa on thecisplatin-induced damage of HEI-OC1 auditory cells through scavenging freeradicals. J Ethnopharmacol 2006; 107:383–388.

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This paper shows a promising trend towards a protective effect of STS onaminoglycoside-induced hearing loss.

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