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Wp seidman 06

  1. 1. Auditory research involving antioxidants Ilaaf Darrat, Nadir Ahmad, Kevin Seidman and Michael D. Seidman Purpose of review Introduction The role of antioxidants in the management of hearing loss The role of antioxidants in attenuating hearing loss has has generated considerable interest over the past several been the subject of much interest, scrutiny, criticism, and years. Research efforts in this field have yielded many new controversy over the past several years. The plethora of insights into the molecular and cellular nature of several research studies in this field attests to the impact that types of hearing impairment, including age-related, noise- antioxidants have had on scientific thought and our induced, and drug-induced hearing loss. The objective of society overall. Over the past year, several studies have this paper is to highlight some of the important studies been published that largely support the role of antiox- published over the past several years that have further idants in reversing or attenuating the deleterious effects contributed to our understanding of the mechanism of of reactive oxygen species (ROS). This trend has been antioxidants in attenuating hearing loss. noted in earlier studies and has been the impetus for Recent findings continuing research efforts in this field. There is compelling evidence to suggest that antioxidant therapy is beneficial in attenuating, improving, or reversing An increase in reactive oxygen species (ROS) production the effects of several types of acquired hearing loss. Cellular is postulated to play an important role in age-related, and subcellular changes resulting from these types of noise-induced, and drug-induced hearing loss. ROS con- hearing impairment are remarkably similar and seem to have tain an unpaired number of electrons, rendering them a common putative mechanism of oxidative stress and chemically reactive and toxic to cellular and subcellular damage. Recent studies have lent further credibility to the structures. ROS have been implicated in the pathophy- notion that antioxidant therapy can be of considerable siologic processes of more than 100 medical conditions benefit in the treatment of hearing loss. The increasing body [1]. They are generated in vivo as a byproduct of mito- of literature pertaining to human studies will shed further chondrial respiration, and are also produced via autoox- light into this fascinating area of research. idation of chemical and biological molecules. ROS Summary are also environmental contaminants and can be formed This review elucidates the role of antioxidants in hearing from ionizing and ultraviolet radiation. The most com- loss and illustrates the continued evolution of research mon ROS are superoxide anion (O2À), hydroxyl radical efforts in this field. (OHÀ), hypochlorite (OClÀ), and nitric oxide (NOÀ). ROS are converted to nonreactive molecules by endogen- Keywords ous cellular enzymes, such as copper/zinc superoxide antioxidants, drug-induced hearing loss, noise-induced dismutase (SOD1), manganese superoxide dismutase hearing loss, NIHL, presbyacusis, reactive oxygen species (SOD2), catalase, and peroxidase. Additionally, the admin- istration of exogenous antioxidants, such as a-lipoic acid, Curr Opin Otolaryngol Head Neck Surg 15:358–363. ß 2007 Lippincott Williams & acetyl-L-carnitine (ALCAR), N-acetylcysteine (NAC), Wilkins. vitamins E and C, and phytochemicals, also results in Department of Otolaryngology, Head and Neck Surgery, Henry Ford Hospital, scavenging of ROS. The medical literature has overwhel- Detroit, Michigan, USA mingly supported the protective effects of antioxidants Correspondence to Michael D. Seidman, MD, FACS, Department of Otolaryngology-Head and Neck Surgery, Director, Division of Otologic/ and ROS scavengers on age-related, noise-induced, and Neurotologic Surgery, Henry Ford Hospital, Director of Complementary/Integrative drug-induced hearing loss. Several studies and review Medicine, 6777 West Maple Road, West Bloomfield, MI 48323, USA Tel: +1 248 661 7211; fax: +1 248 661 6456; e-mail: mseidma1@hfhs.org articles from the senior author’s laboratory have helped to elucidate some of the molecular events leading to these Current Opinion in Otolaryngology & Head and Neck Surgery 2007, 15:358–363 various types of acquired hearing loss, as well as to identify specific antioxidants that have significant beneficial effects Abbreviations on hearing loss [2–9]. ALCAR acetyl-L-carnitine DPOAE distortion product otoacoustic emission MHA membrane hypothesis of aging NAC N-acetylcysteine Antioxidants in age-related hearing loss NIHL noise-induced hearing loss Presbyacusis is the progressive, high frequency, sensor- ROS reactive oxygen species SRG steamed roots of Rehmannia glutinosa ineural hearing loss that occurs with advancing age. The STS sodium thiosulphate accumulation of ROS is strongly implicated in the aging ß 2007 Lippincott Williams & Wilkins process and is regarded as an important deleterious 1068-9508 event in the genesis of presbyacusis [10]. The persistent 358 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. Auditory research involving antioxidants Darrat et al. 359 interaction of ROS with cellular and subcellular Additionally, these ROS result in lipid peroxidation, (i.e. mitochondrial) structures ultimately leads to tissue polysaccharide depolymerization, nucleic acid disrup- damage and cell death. The National Institutes of tion, and oxidation of sulfhydryl groups, leading to Health has estimated that approximately 30–35% of enzyme inactivation [14]. Hence, the MHA suggests that adults between the ages of 65 and 75 years have some ROS induced cell membrane structural damage is the degree of hearing loss [11]. Furthermore, approximately primary mediating event in cellular aging [15,16]. It is 40–50% of people aged 75 years and older have hearing plausible that various aspects of these theories occur in loss that can impair communication. concert and serve to better explain the aging process. For example, ROS generation leads to genetic and Numerous hypotheses have been advocated to explain cellular alterations resulting in cellular dysfunction, the mechanisms of the aging process. These can be and consequently to senescence. broadly grouped into two categories: those that impli- cate deterministic, or ‘programmed’, alterations in gene Significant progress has been made to identify the mol- expression or gene structure; and those that implicate ecular mechanisms of age-related hearing loss. This in a variety of stochastic or ‘random’ alterations in the turn has led to research on methods of mitigating the structure and function of macromolecules, cells and adverse effects on the auditory system. Understanding of organ systems. The corresponding author’s laboratory the relevant mechanisms of aging provides a potential and others have also provided compelling evidence that roadmap for interventional therapeutic strategies to coun- diseases associated with the aging process result from the teract the processes of aging. There is increasing evi- accumulation of ROS. ROS directly damages subcellular dence suggesting that ROS have a putative role in the structures, such as mitochondrial DNA (mtDNA), creating damage associated with cochlear ischemia, noise trauma, deletions and mutations, subsequently producing bio- aging, presbyacusis, and ototoxicity. energetically deficient cells. This cascade of events leads to senescence, cell death, and hearing loss. Senescence is The focus of the corresponding author’s laboratory is to the progressive accumulation of metabolic and physio- elucidate the mechanisms of aging, specifically the role logic derangements, which increases susceptibility to that ROS plays in this process. The aging process partly disease. Several theories have been proposed to explain occurs due to oxidative stress, resulting in increased the phenomenon of senescence. The most convincing mitochondrial DNA mutations, and a concomitant theories are the telomerase theory of aging, the dysdiffer- reduction in mitochondrial function. These changes entiation hypothesis of aging, and the membrane ultimately lead to cellular and subcellular dysfunction, hypothesis of aging (MHA), also referred to as the which likely manifests in the inner ear milieu as a mitochondrial clock theory of aging. significant decrease in auditory sensitivity. The gener- ation of these ROS is partly responsible for the In the telomerase theory of aging, a reduction in telomere reduction in the mitochondrial membrane potential length occurs over time. The end of a chromosome is and the loss of cochlear hair cells, with an attendant composed of a structure called the telosome, the tip of increase in the auditory threshold. These deleterious which is the telomere. Reduction in the length of the effects of aging can be slowed and in some situations telomere and alterations in its chromatin assembly may even reversed through strategies that affect the bio- account for the instability that occurs during senescence energetic properties of cells. In 2000, a study published [12]. It has been suggested that the balance between from our laboratory demonstrated significant protec- telomere shortening and telomerase activity may underlie tive effect in auditory thresholds in subjects either various cellular aging processes. treated with specific antioxidants or caloric restriction. The results of this 5-year series of experiments In the dysdifferentiation theory, aging occurs on a con- represented the first prospective randomized trial tinuum of programmed differentiation leading to either a designed to investigate the effect of antioxidants, nutri- cessation of normal gene activity or a systematic acti- tional supplementation and dietary restriction on hearing vation of genes whose effects are deleterious to cellular loss specifically and aging in general. This study and function. earlier ones were the first to propose that the mechanism involving the generation of ROS and resultant damage to The MHA suggests that aging is related to a decreased mitochondria may be responsible for presbyacusis effectiveness of cellular protective and reparative mech- [2,3,5]. The findings from these experiments demon- anisms, yielding biochemical and metabolic errors that strated that dietary restriction and specific nutrient progressively accumulate, resulting in eventual cell death supplementation reduce the progression of age-related [13]. Furthermore, the MHA postulates that cellular hearing loss [5]. This beneficial effect was thought to senescence is attributable to the cross-linking action likely represent a reduction in oxidative stress through of ROS or radicals within the cellular membrane. antioxidant therapy. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. 360 Hearing science In the past year, several studies have corroborated the and the military, it also occurs as a result of recreational evidence accumulated from previous years and those pursuit exposure, such as using personal listening obtained from our laboratory. In a recent article by de devices. Acoustic trauma can be tremendous enough to Rivera et al. [17], the effect of blueberry phytochemical, cause mechanical disruption of the cochlea resulting in an antioxidant, on the speed of temporal processing in immediate, permanent hearing loss. Most clinical primary auditory cortex aged rats was investigated. This scenarios, however, are due to a gradual hearing loss, study showed that the frequency modulated sweep in the which results from cumulative oxidative metabolic stress aged rats that had been fed a blueberry-enriched diet for and damage. Considerable research [19] has been 8 weeks was faster than aged rats that had been feed corn aimed at investigating antioxidants to treat or prevent pellet or normal rat chow pellets. Furthermore, the aged the onset or progression of NIHL. The senior author has rats that were fed the blueberry-enriched diet had a faster studied the effects of resveratrol, a phytoalexin and frequency modulated sweep than young rats. This was nutritional supplement found in the skin of red grapes, the first study to investigate the effects of blueberry on acoustic trauma. In a study published in 2003, resver- phytochemicals on sensory processing. Le and Keithley atrol supplementation was noted to reduce threshold [18] investigated the effects of an antioxidant-rich diet in shifts in young rats exposed to significant acoustic trauma beagle dogs on age-related cochlear structural changes. (105 dB over a range of 4500–9000 Hz, for 24 h) compared They found that the dogs that were fed a diet rich in to a similar group of rats supplemented only with normal vitamin E, L-carnitine, DL-a-lipoic acid, and vitamin C saline [20]. in the last 3 years of their lives exhibited a greater neuronal density in the apical turn of the spiral ganglion With massive noise stimulation, an excessive amount of versus an age-matched control group. When these anti- glutamate, a neurotransmitter at the junction of the inner oxidant-enriched dogs were compared with a younger hair cells and afferent neuron in the peripheral auditory group of dogs, there was no difference in the neuronal system, is released resulting in ionic influx and massive density between the two. In addition, when comparing entry of water and extracellular calcium into the afferent the stria vascularis thickness in the antioxidant-enriched neurons, causing cell death and noise induced hearing aged dogs versus the age-matched control group, there loss [21,22]. Duan et al. [23] investigated the protective was a larger amount of neuronal degeneration at the basal effect of caroverine, an antioxidant and an antagonist and apical ends of the cochlea in the age-matched control of two glutamate receptors, against acoustic trauma in group. The stria vascularis is rich in mitochondria. rats. The rats were divided into two groups, one that was Exposure to ROS results in degradation of the mitochon- pretreated with administration of subcutaneous carover- dria, thus contributing to age-related ultrastructural ine for 72 h, and a second group given subcutaneous changes in the cochlea. Auditory thresholds were not saline. After 48 h, each group was exposed to impulse obtained during this study, however, thus conclusions noise at 160 dB. The study revealed that prior to about resultant hearing differences would be speculative. impulse noise insult, subcutaneously administered Nevertheless, these types of studies offer significant caroverine decreased impulse noise-induced hearing promise for the treatment of presbyacusis. Research loss in rats. An antioxidant that has been extensively efforts need to be directed to performing prospective studied in relation to NIHL is NAC. NAC stimulates the randomized studies in humans to more convincingly production of the major cellular antioxidant, glutathione demonstrate the beneficial and powerful effect of anti- in hair cells [24], acts as a free radical scavenger, and oxidants on age-related hearing loss. These studies, how- inhibits cell death pathway enzymes [25–28]. Coleman ever, provide encouraging evidence that antioxidants et al. [29] investigated the protective effect of NAC 1, 4, may slow down, reverse or improve the process of age- and 12 h after NIHL in chinchillas. The animals were related hearing loss. The research on antioxidants and divided into three groups: those administered a saline their role in attenuating or reversing the effects of age- control, those supplemented with NAC, and those given related hearing loss is compelling and overwhelmingly ALCAR (a mitochondrial bio-energy maintenance and positive. Our contention is a diet rich in certain specific integrity compound). The animals were first exposed to antioxidants should be offered to all patients experien- 6 h of 105 dB sound-pressure level octave band noise cing age-related hearing loss. centered at 4000 Hz. One hour after noise exposure, the greatest decrease in hearing loss was noted in the Antioxidants in noise-induced hearing loss NAC and ALCAR supplemented groups. There was no Noise-induced hearing loss (NIHL) is a type of high- improvement in hearing, however, when NAC and frequency sensorineural hearing loss, often with a classic ALCAR were administrated 12 h after noise exposure. notch at 4000 Hz. It is a preventable cause of hearing loss caused by excessive exposure to either acute or chronic To determine the effect of NAC on NIHL in humans, acoustic trauma. Though NIHL is usually associated with as the other studies described herein have been in occupational exposure such as in the automotive industry animals, Kramer et al. [30] performed a randomized, Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. Auditory research involving antioxidants Darrat et al. 361 double-blinded, placebo-controlled study. Distortion resolve inner ear symptoms is the ethanol extract of the product otoacoustic emission (DPOAE) measurements steamed roots of Rehmannia glutinosa Liboschitz (SRG) were performed on the participants before and 2 h after [40]. Yu et al. [41] investigated the dose of SRG that would exposure to live music at a nightclub. The participants prevent cisplatin ototoxicity. HEI-OCI auditory cells were were either given a 900 mg tablet of NAC or a placebo pretreated with 0, 5, 10, 50 and 100 mg/ml of SRG for 1 h, 30 min before noise exposure. No statistical significance after which cisplatin was added to each cell culture. was seen in either group in DPOAE measurements. SRG prevented cisplatin-induced lipid peroxidation in a dose-dependent manner. In addition, it was found that Though the study did not show a protective benefit of SRG acts as a free radical scavenger by removing ROS, NAC in humans, it is still believed that taking NAC more specifically, hydrogen peroxide, hydroxyl radical, before noise exposure is beneficial. A randomized, and 1,1-dipheny-2-picrylhydrazyl (DPPH) radicals. To double-blinded, placebo controlled study in humans that determine the protective effects of sodium thiosulphate investigated the effect of NAC at different doses and on gentamicin-induced hearing loss, Hochman et al. [42] varying time schedules still needs to be performed to investigated the effects on C57 mice. There were four demonstrate a statistically significant protective effect of groups: a group receiving intraperitoneal injection of only NAC in NIHL. gentamicin, a group receiving injection of only sodium thiosulphate, a group receiving injection of both of gen- Antioxidants in drug-induced hearing loss tamicin and sodium thiosulphate, and a group injected Platinum based chemotherapeutic agents and aminogly- with normal saline. Auditory brainstem response (ABR) cosides have been shown to be ototoxic, often resulting in thresholds were recorded at initiation of the study and then bilateral, symmetric sensorineural hearing loss. Of the on day 35. Though the results showed a promising trend platinum based agents, cisplatin is more commonly and towards a protective effect of sodium thiosulphate, it was classically associated with ototoxicity, though carboplatin not statistically significant. has also been shown to be ototoxic. Coling et al. [31] identified three of the five cochlear proteins that are These studies suggest that antioxidants can protect upregulated and four of the 17 cochlear proteins that against drug-induced hearing loss, though further studies are downregulated with cisplatin treatment causing oto- are needed to clearly advocate the routine prophylactic toxicity. Cisplatin administration results in ROS gener- and therapeutic use of antioxidants in drug-induced ation, [32] causing an increase in lipid peroxidation of cell hearing loss. The platinum based chemotherapeutic membranes, which results in outer hair cell damage [33]. agents and aminoglycosides are widely used and thus The effects of cisplatin ototoxicity also manifest in the further evidence to clearly support or demonstrate a organ of Corti, spiral ganglion cells, and the stria vascu- positive trend is needed to allow for widespread accep- laris. The damage that is caused to the organ of Corti is tance of antioxidant use with administration of these permanent, but the damage to the stria vascularis is potentially deleterious drugs. transient. Similarly, aminoglycosides directly damage the outer hair cell membrane. Though the mechanism Conclusion of action is not completely understood, ROS production The role of antioxidants in the management of age- has been suggested as a causative factor [34–36]. related, noise-induced and drug-induced hearing loss continues to evolve and be elucidated. Studies published Sodium thiosulphate (STS), a reactive thiol compound, in the last several years have yielded promising results has been investigated extensively and found to reduce and are strongly suggestive of a protective role for these ototoxicity caused by cisplatin in mice and guinea pigs compounds. These studies have been largely limited to [37–38]. STS acts by binding and inactivating the animal models and the research focus clearly needs to platinum-containing DNA alkylating agents, and by act- shift to more randomized, placebo-controlled, double- ing as a free radical scavenger. This results in otoprotec- blinded studies in humans. Nevertheless, results from an tion from cisplatin and carboplatin [39]. It has been overwhelming majority of studies on antioxidants and shown, however, that co-administration of sodium thio- acquired hearing loss demonstrate the beneficial effects sulphate and cisplatin can reduce the antitumor effects of of these compounds at a cellular and subcellular level, as cisplatin [37]. Neuwelt et al. [39] investigated carbopla- well as in objective measures of hearing sensitivity, such tin and ototoxicity in children. The objective of their as ABR testing. Two recent studies presented at the study was to determine whether delaying STS adminis- Combined Otolaryngology Sections Meeting (COSM) tration 4 h after carboplatin would be protective in in San Diego (April 2007) highlight the continued 12 children treated for a brain tumor. Though the data research efforts in the field of antioxidant therapy. A were not statistically significant, owing to a small sample study directed by Kopke et al. [43] investigated the role size, it was determined that high dose STS was safe in of oral NAC administration given during weapons train- children. A natural antioxidant that has been found to ing in the Marine Corps; 566 subjects were enrolled in the Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  5. 5. 362 Hearing science study, of which 289 were given placebo and 277 given 11 National Institute of Aging. Hearing Loss. Age Page. www.niapublications. org/agepages/hearing.asp. Bethesda: U.S. Department of Health and NAC. The subjects received 900 mg/day of NAC or Human Services, National Institutes of Health; September 2002; Reprinted placebo for 16 days. Hearing status was evaluated prior August 2005. to and 10 days following the 16-day weapons training, 12 Hockenberry DM, Otlvai ZN, Yin XM, et al. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993; 75:241–252. using pure-tone audiometry and DPOAEs. The results 13 Sohal RS, Allen RG. Relationship between metabolic rate, free radicals, demonstrated a significant effect of NAC in reducing differentiation and aging: a unified theory. Basic Life Sci 1985; 35:75–104. the significant threshold shift in ears exposed to more 14 Southorn PA, Powis G. Free radicals in medicine, I: chemical nature and intense acoustic trauma at the dose used. The conclusion biologic reactions. Mayo Clin Proc 1988; 63:381–389. was that oral NAC was safe and effective [43]. Another 15 Zs-Nagy I, Semsei I. Centrophenoxine increases the rates of total and mRNA synthesis in the brain cortex of old rats: an explanation of its action in terms of the study presented by Choi et al. [44] looked at the effec- membrane hypothesis of aging. Experimental Gerontol 1984; 19:171–178. tiveness of combinations of antioxidant compounds 16 Zs-Nagy I. CRC handbook of free radicals and antioxidants in biomedicine. in the treatment of acute acoustic trauma. In the study, Boca Raton: CRC Press; 1989. 17 de Rivera C, Shukitt-Hale B, Joseph JA, Mendelson JR. The effects of three groups of chinchillas (six per group) were exposed antioxidants in the senescent auditory cortex. Neurobiol Aging 2006; 27: to 105 dB narrow-band noise centered at 4 kHz for 6 h. 1035–1044. This paper was the first study to investigate the effects of blueberry phytochem- These groups were administered different antioxidant icals on sensory processing. compound combinations and at different doses. The 18 Le T, Keithley EM. Effects of antioxidants on the aging inner ear. Hear Res antioxidants studies were NAC, ALCAR and hydroxyl- 2007; 226:194–202. This paper illustrates the importance of an antioxidant rich diet on the auditory ated a-phenyl-tert-butylnitrone (4-OH-PBN). The system. results demonstrated that the chinchillas administered 19 Le Prell CG, Yamashita D, Minami SB, et al. Mechanisms of noise-induced the two types of drug combinations and at different doses hearing loss indicate multiple methods of prevention. Hear Res 2007; 226:22–43. had their permanent threshold shifts completely elimi- This is an excellent comprehensive review of the mechanism of NIHL and anti- nated as opposed to the chinchillas given a control carrier oxidant effects on NIHL. solution [44]. These results support the judicious use of 20 Seidman M, Babu S, Tang W, et al. Effects of resveratrol on acoustic trauma. Otolaryngol Head Neck Surg 2003; 129:463–470. antioxidants in individualized cases of acquired hearing 21 Duan M, Agerman K, Ernfors, Canlon B. Complementary roles of neurotrophin loss. The medical practitioners’ understanding of the 3 and an N-methyl-D-aspartate antagonist in the protection of noise and aminoglycoside-induced ototoxicity. Pro Natl Acad Sci U S A 2000; literature regarding antioxidant use in hearing loss and 97:7597–7602. recognition of the risks, benefits and alternatives of this 22 Spoendlin H. Primary structural changes in the organ of corti after acoustic type of therapy is paramount to appropriate management overstimulation. Acta Otolaryngol (Stockh) 1971; 71:166–176. and counseling of patients. 23 Duan M, Chen Z, Qiu J, et al. Low-dose, long-term caroverine administration attenuates impulse noise-induced hearing loss in the rat. Acta Otolaryngo- logica 2006; 126:1140–1147. This paper investigates the use of low-dose, long-term caroverine as a novel drug References and recommended reading to protect against NIHL. Papers of particular interest, published within the annual period of review, have 24 De Rosa SC, Zaretsky MD, Dubs JG, et al. N-acetylcysteine replenishes been highlighted as: glutathione in HIV infection. Eur J Clin Invest 2000; 30:915–929. of special interest of outstanding interest 25 Eilers A, Whitfield J, Vekrelis K, et al. C-Jun and Bax: regulators of pro- grammed cell death in developing neurons. Biochem Soc 1999; 27:790–797. Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 377). 26 Kopke RD, Coleman JK, Liu J, et al. Candidate’s thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss. Laryngo- 1 Halliwell B, Gutteridge JM, Cross CE. Free radicals, antioxidants, and human scope 2002; 112:1515–1532. disease: where are we now? J Lab Clin Med 1992; 119:589–620. 27 Kopke RD, Weisskopf PA, Boone JL, et al. Reduction of noise-induced 2 Seidman MD, Bai U, Khan MJ, Quirk WS. Mitochondrial deletions associated hearing loss using L-NAC and salicylate in the chinchilla. Hear Res 2000; with aging and presbyacusis. Arch Otolaryngol Head Neck Surg 1997; 149:138–146. 123:1039–1045. 28 Kopke R, Allen KA, Henderson D, et al. A radical demise. Toxins and trauma 3 Bai U, Seidman MD, Hinojosa R, Quirk WS. Mitochondrial DNA deletions share common pathways in hair cell death. Ann N Y Acad Sci 1999; associated with aging and possibly presbyacusis: a human archival temporal 884:171–191; Review. bone study. Am J Otol 1997; 18:559–563. 29 Coleman JK, Kopke RD, Liu J, et al. Pharmacological rescue of noise induced 4 Seidman MD, Khan MJ, Bai U, et al. Biological activity of mitochondrial hearing loss using N-acetylcysteine and acetyl-L-carnitine. Hear Res 2007; metabolites on aging and age-related hearing loss. Am J Otol 2000; 21: 226:104–113. 161–167. This excellent paper illustrates how treating NIHL with a combination of NAC and ALCAR is promising. 5 Seidman MD. Effects of dietary restriction and antioxidants on presbyacusis. Laryngoscope 2000; 110 (5pt1):727–738. 30 Kramer S, Dreisbach L, Lockwood J, et al. Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music. J Am Acad 6 Seidman MD, Shirwany N, Quirk WS. Mechanisms of alteration in the Audiol 2006; 17:265–278. microcirculation of the cochlea. Ann N Y Acad Sci 1999; 884:226–232. This interesting paper showing promise for the use of antioxidants in treating NIHL 7 Seidman MD, Ahmad N, Bai U. Molecular mechanisms of age-related hearing in human subjects. loss. Ageing Res Rev 2002; 1:331–343. 31 Coling DE, Ding D, Young R, et al. Proteomic analysis of cisplatin-induced 8 Seidman MD, Khan MJ, Tang WX, Quirk WS. Influence of lecithin on cochlear damage: Methods and early changes in protein expression. Hear Res mitochondrial DNA and age-related hearing loss. Otolaryngol Head Neck 2007; 226:140–156. Surg 2002; 127:138–144. This comprehensive paper illustrates the first use of contemporary proteomic analysis in cochlear pathology. 9 Seidman MD, Ahmad N, Joshi D, et al. Age-related hearing loss and its association with reactive oxygen species and mitochondrial DNA damage. 32 Halliwell B. Antioxidants in human health and disease. Annu Rev Nutr 1996; Acta Otolaryngol Suppl 2004; 552:16–24. 16:33–50. 10 Head E, Liu J, Hagen TM, et al. 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  6. 6. Auditory research involving antioxidants Darrat et al. 363 34 Garetz SL, Altschuler RA, Schacht J. Attenuation of gentamicin ototoxicity by 40 Yuk Cs, Ahn DK. Modern herbalogy. Seoul: Komonsa; 1972. glutathione in the guinea pig in vivo. Hear Res 1994; 77:81–87. 41 Yu HH, Seo SJ, Kim YH, et al. Protective effect of Rehmannia glutinosa on the 35 Schacht J. Aminoglycoside ototoxicity: prevention in sight? Otolaryngol Head cisplatin-induced damage of HEI-OC1 auditory cells through scavenging free Neck Surg 1998; 118:674–677. radicals. J Ethnopharmacol 2006; 107:383–388. This paper investigates the dose of SRG that would prevent cisplatin ototoxicity. 36 Takumida M, Popa R, Anniko M. Free radicals in the guinea pig inner ear following gentamicin exposure. ORL J Otorhinolaryngol Relat Spec 1999; 61: 42 Hochman J, Blakley BW, Wellman M, Blakley L. Prevention of aminoglycoside- 63–70. induced sensorineural hearing loss. J Otolaryngol 2006; 35:153–156. 37 Viallet NR, Blakley BW, Begleiter A, Leith MK. Sodium thiosulphate impairs This paper shows a promising trend towards a protective effect of STS on the cytotoxic effects of cisplatin on FADU cells in culture. J Otolaryngol 2005; aminoglycoside-induced hearing loss. 35:19–21. 43 Kopke R, Balough BJ, Lonsbury-Martin B, Slade M, et al. Pharmacological 38 Leitao DJ, Blakley BW. Quantification of sodium thiosulphate protection on prevention of noise induced hearing loss [abstract]. In: Presentations of the cisplatin-induced toxicities. J Otolaryngol 2003; 32:146–150. American Otological Society Meeting, COSM meeting. 26–29 April 2007; San Diego. Omaha: The Triological Society; 2007. 39 Neuwelt EA, Gilmer-Knight K, Lacy C, et al. Toxicity profile of delayed high dose sodium thiosulfate in children treated with carboplatin in conjuction 44 Choi C, Chen K, Vasquez-Weldon A, Jackson RJ, et al. Effectiveness of with blood-brain-barrier disruption. Pedatr Blood Cancer 2006; 47:174– combinations of antioxidant drugs in the treatment of acute acoustic trauma 182. [abstract]. In: Presentations of the American Otological Society Meeting, This paper investigates the protective effect of STS on carboplatin-induced COSM meeting. 26–29 April 2007; San Diego. Omaha: The Triological hearing loss in children. Society; 2007. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.