Oxidative Cochlear Injury and the Limitations of Antioxidant Therapy

ABSTRACT

Evidence has been amassed over the last 15 years implicating reactive oxygen species (ROS) in cochlear injury due to ischemia, noise, and ototoxicants. Because ROS appear to be broadly involved in most cellular injury processes, it might be expected that antioxidants applied with optimal timing, dose, and route should completely prevent cochlear injury. This expectation has remained unmet, however. Recent experiments involving noise injury in knockout mice for key antioxidant enzymes also have yielded surprisingly modest, even paradoxical, results. Research in the area of oxidative stress and deafness is moving into a more mature phase, wherein simplistic models and hypotheses are being modified to include more of the emerging complexity of reduction-oxidation (redox) biochemistry. Sensory cell injury and death probably includes parallel ROS-dependent and ROS-independent pathways. In addition, ROS-related processes are complex and include myriad checks and balances, such that the manipulation of a single component can produce unexpected results. Varied cochlear cell types and epithelia may differ in antioxidant capacity or sustain injury through different ROS-mediated cascades. Finally, some ROS serve as messengers, both under normal circumstances and as cells strive to maintain homeostasis after stress. Antioxidant therapy in some form nevertheless retains promise for protecting the cochlea from acute and chronic stress. Consideration of ROS within an appropriately broad cell biological context may favor combined pharmacological remedies.

KEYWORDS

Cochlea - noise-induced hearing loss - ototoxicants - reactive oxygen species - free radicals - antioxidants - mitochondria

REFERENCES

• 1 Halliwell B. Reactive oxygen species and the central nervous system.  J Neurochem . 1992;  59 1609-1623
• 2 Götz M E, Kunig G, Riederer P, Youdim M BH. Oxidative stress: free radicals production in neural degeneration.  Pharm Ther . 1994;  63 37-122
• 3 Michiels C, Raes M, Toussaint O, Remacle J. Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress.  Free Radic Biol Med . 1994;  17 235-248
• 4 Finkel T. Signal transduction by reactive oxygen species in non-phagocytic cells.  J Leukoc Biol . 1999;  65 337-340
• 5 Rhee S G. Redox signaling: Hydrogen peroxide as intracellular messenger.  Exp Mol Med . 1999;  31 53-59
• 6 Schafer F Q, Buettner G R. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.  Free Radic Biol Med . 2001;  30 1191-1212
• 7 Beal M F. Aging, energy, and oxidative stress in neurodegenerative diseases.  Ann Neurol . 1995;  38 357-366
• 8 Dulon D, Zajic G, Schacht J. Photo-induced irreversible shortening and swelling of isolated cochlear outer hair cells.  Int J Radiat Biol . 1989;  55 1007-1014
• 9 Ikeda K, Sunose H, Takasaka T. Effects of free radicals on the intracellular Calcium concentration in the isolated outer hair cell of the guinea pig cochlea.  Acta Otolaryngol . 1993;  113 137-141
• 10 Seidman M D, Quirk W S. The protective effects of tirilated mesylate (U74006F) on ischemic and reperfusion-induced cochlear damage.  Otolaryngol Head Neck Surg . 1991;  105 511-516
• 11 Seidman M D, Quirk W S, Nuttall A L, Schweintzer V G. The protective effects of allopurinol and superoxide dismutase-polyethylene glycol on ischemic and reperfusion-induced cochlear damage.  Otolaryngol Head Neck Surg . 1991;  105 457-463
• 12 Garetz S L, Altschuler R A, Schacht J. Attenuation of gentamicin ototoxicity by glutathione in the guinea pig in vivo.  Hear Res . 1994;  77 81-87
• 13 Garetz S L, Rhee D J, Schacht J. Sulfhydryl compounds and antioxidants inhibit cytotoxicity to outer hair cells of a gentamicin metabolite in vitro.  Hear Res . 1994;  77 75-80
• 14 Quirk W S, Shivapuja B G, Schwimmer C L, Seidman M D. Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts.  Hear Res . 1994;  74 217-220
• 15 Campbell K CM, Rybak L P, Meech R P, Hughes L. D-methionine provides excellent protection from cisplatin ototoxicity in the rat.  Hear Res . 1996;  102 90-98
• 16 Clerici W J. Effects of superoxide dismutase and U74389G on acute trimethylin-induced cochlear dysfunction.  Toxicol Appl Pharmacol . 1996;  136 236-242
• 17 Hu B H, Zheng X Y, McFadden S, Henderson D. The protective effects of R-PIA on noise-induced hearing loss.  Hear Res . 1997;  113 198-206
• 18 Rybak L P, Husain K, Whitworth C, Somani S M. Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.  Toxicol Sci . 1999;  47 195-202
• 19 Yamasoba T, Schacht J, Shoji F, Miller J M. Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line derived neurotrophic factor in vivo.  Brain Res . 1999;  815 317-325
• 20 Kopke R D, Weisskopf P A, Boone J L. Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla.  Hear Res . 2000;  149 138-146
• 21 Sha S, Schacht J. Antioxidants attenuate gentamicin-induced free radical formation in vivo: D-methionine is a potential protectant.  Hear Res . 2000;  142 34-40
• 22 Yamane H, Nakai Y, Takayama M. Appearance of free radicals in the guinea pig Inner ear after noise-induced acoustic trauma.  Eur Arch Otorhinolaryngol . 1995;  252 504-508
• 23 Clerici W J, Hensley K, DiMartino D L, Butterfield D A. Direct detection of ototoxicant-induced reactive oxygen species generation in cochlear explants.  Hear Res . 1996;  98 116-124
• 24 Hirose K, Hockenbery D M, Rubel E W. Reactive oxygen species in chick hair cells after gentamicin exposure in vitro.  Hear Res . 1997;  104 1-14
• 25 Kopke R D, Liu W, Gabaizedah R. 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
• 26 Ohlemiller K K, Dugan L L. Elevation of reactive oxygen species following ischemia-reperfusion in mouse cochlea observed in vivo.  Audiol Neurootol . 1999;  4 219-228
• 27 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
• 28 Hara A, Serizawa F, Tabuchi K, Senarita M, Kusakari J. Hydroxyl radical formation in the perilymph of asphyxic guinea pig.  Hear Res . 2000;  143 110-114
• 29 Clerici W J, Yang L. Direct effects of intraperilymphatic reactive oxygen species generation on cochlear function.  Hear Res . 1996;  101 14-22
• 30 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
• 31 Jacono A A, Hu B, Kopke R D. Changes in cochlear antioxidant enzyme activity after sound conditioning and noise exposure in the chinchilla.  Hear Res . 1998;  117 31-38
• 32 Yamasoba T, Harris C, Shoji F. Influence of intense sound exposure on glutathione synthesis in the cochlea.  Brain Res . 1998;  804 72-78
• 33 Willott J F. Aging and the Auditory System: Anatomy, Physiology, and Psychophysics. San Diego, CA: Singular Publishing Group; 1991
• 34 Schuknecht H F. Pathology of the Ear, 2nd ed. Philadelphia, PA: Lea & Febiger; 1993. 
• 35 Erway L C, Willott J F, Archer J R, Harrison D E. Genetics of age-related hearing loss in mice. I. Inbred and F1 hybrid strains.  Hear Res . 1993;  65 125-132
• 36 Erway L C, Shiau Y-W, Davis R R, Kreig 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
• 37 Johnson K R, Erway L C, Cook S A, Willott J F, Zheng Q Y. A major gene affecting age-related hearing loss in C57BL/6J mice.  Hear Res . 1997;  114 83-92
• 38 Ohlemiller K K, Wright J S, Heidbreder A F. Vulnerability to noise-induced hearing loss in 'middle-aged' and young adult mice: A dose-response approach in CBA, C57BL, and BALB inbred strains.  Hear Res . 2000;  149 239-247
• 39 Stoian I, Oros A, Moldoveanu E. Apoptosis and free radicals.  Biochem Mol Med . 1996;  59 93-97
• 40 McFadden S L, Ding D, Burkard R F. Cu/Zn SOD deficiency potentiates hearing loss and cochlear pathology in aged 129,CD-1 mice.  J Comp Neurol . 1999;  413 101-112
• 41 McFadden S L, Ding D, Reaume A G, Flood D G, Salvi R J. Age-related cochlear hair cell loss is enhanced in mice lacking copper/zinc superoxide dismutase.  Neurobiol Aging . 1999;  20 1-8
• 42 Ohlemiller K K, McFadden S L, Ding D-L. Targeted deletion of the cytosolic Cu/Zn-superoxide dismutase gene (SOD1) increases susceptibility to noise-induced hearing loss.  Audiol Neurootol . 1999;  4 237-246
• 43 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
• 44 McFadden S L, Ding D-L, Ohlemiller K K, Salvi R J. The role of superoxide dismutase in age-related and noise-induced hearing loss: clues from Sod1 knockout mice. In: Willott JF, ed. Handbook of Mouse Auditory Research: From Behavior to Molecular Biology New York: CRC Press 2001: 489-504
• 45 Evans P, Halliwell B. Free radicals and hearing: cause, consequence and criteria.  Ann N Y Acad Sci . 1999;  884 19-40
• 46 Kopke R, Allen K A, Henderson D. A radical demise: toxins and trauma share common pathways in hair cell death.  Ann N Y Acad Sci . 1999;  884 171-191
• 47 Slepecky N. Overview of mechanical damage to the inner ear: noise as a tool to probe cochlear function.  Hear Res . 1986;  22 307-321
• 48 Saunders J C, Cohen Y E, Szymko Y M. The structural and functional consequences of acoustic injury in the cochlea and peripheral auditory system.  J Acoust Soc Am . 1991;  90 136-146
• 49 Mignotti B, Vayssiere J-L. Mitochondria and apoptosis.  Eur J Biochem . 1998;  252 1-15
• 50 Reser D, Rho M, Dewan D. L- and D-methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro retention of antineoplastic activity.  Neurotoxicology . 1999;  20 731-748
• 51 Huang T, Cheng A G, Stupak H. Oxidative stress-induced apoptosis of cochlear sensory cells: otoprotective strategies.  Int J Dev Neurosci . 2000;  18 259-270
• 52 Stockwell C W, Ades H, Engstrom H. Patterns of hair cell damage after intense noise stimulation.  Ann Otol . 1969;  78 1144-1168
• 53 Martinez C S, Bohne B A, Harding G W. Moderate noise-induced TTSs correlate best with injury to supporting cells rather than hair cells.  Abstr Assoc Res Otolaryngol . 2000;  23 44
• 54 McConkey D J, Orrenius S. Signal transduction pathways in apoptosis.  Stem Cells . 1996;  14 619-631
• 55 Lefebvre P P, Van De Water T. Connexins, hearing and deafness: clinical aspects of mutations in the connexin 26 gene.  Brain Res Rev . 2000;  32 159-162
• 56 Todt I, Ngezahayo A, Ernst A, Kolb H-A. Inhibition of gap junctional coupling in cochlear supporting cells by gentamicin.  Pflugers Arch . 1999;  438 865-867
• 57 Iurato S. Submicroscopic Structure of the Inner Ear. New York: Pergamon Press; 1967
• 58 Wangemann P, Schacht J. Homeostatic mechanisms in the cochlea. In: Dallos P, Popper AN, Fay RD, eds. The Cochlea New York: Springer-Verlag 1996: 130-185
• 59 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
• 60 Kettle A, Sha S, Schacht J. Cochlear base-to-apex differences in free radical mechanisms.  Abstr Assoc Res Otolaryngol . 2001;  24 132
• 61 Sha S, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals.  Hear Res . 2001;  155 1-8
• 62 Ogita K, Matsunobu T, Schacht J. Acoustic trauma enhances DNA binding of transcription factor AP-1 in the guinea pig inner ear.  Neuroreport . 2000;  11 859-862
• 63 Matsunobu T, Ogita K, Osaka H, Schacht J. Modulation of cellular AP-1 DNA binding activity by acoustic overstimulation in the guinea pig cochlea.  Abstr Assoc Res Otolaryngol . 2001;  24 148
• 64 Harman D. Aging: a theory based on free radical and radiation chemistry.  J Gerontol . 1956;  11 98-300
• 65 Sastre J, Pallardo F V, De La Asuncion G J, Vina J. Mitochondria, oxidative stress and aging.  Free Radic Res . 2000;  32 189-198
• 66 Seidman M D, Bai U, Mumtaz J K, Quirk W S. Mitochondrial DNA deletions associated with aging and presbyacusis.  Arch Otolaryngol Head Neck Surg . 1997;  123 1039-1045
• 67 Seidman M D. Effects of dietary restriction and antioxidants on presbyacusis.  Laryngoscope . 2000;  110 727-738