NAC for noise: From the bench top to the clinic

Noise-induced hearing loss (NIHL) is an important etiology of deafness worldwide. Hearing conservation programs are in place and have reduced the prevalence of NIHL, but this disorder is still far too common. Occupational and recreational pursuits expose people to loud noise and ten million persons in the US have some degree of noise-induced hearing impairment. It is estimated that 50 million in the US and 600 million people worldwide are exposed to noise hazards occupationally. Noise deafness is still an important and frequent cause of battlefield injury in the US military. A mainstay of hearing conservation programs is personal mechanical hearing protection devices which are helpful but have inherent limitations. Research has shown that oxidative stress plays an important role in noise-induced cochlear injury resulting in the discovery that a number of antioxidant and cell death inhibiting compounds can ameliorate deafness associated with acoustic trauma. This article reviews one such compound, N-acetylcysteine (NAC), in terms of its efficacy in reducing hearing loss in a variety of animal models of acute acoustic trauma and hypothesizes what its therapeutic mechanisms of action might be based on the known actions of NAC. Early clinical trials with NAC are mentioned.

[1]  N. Slepecky.  Overview of mechanical damage to the inner ear: noise as a tool to probe cochlear function , 1986, Hearing Research.

[2]  D. Henderson,et al.  Intense noise-induced apoptosis in hair cells of guinea pig cochleae. , 2000, Acta oto-laryngologica.

[3]  J. Virkkala,et al.  Rescue of Hearing, Auditory Hair Cells, and Neurons by CEP-1347/KT7515, an Inhibitor of c-Jun N-Terminal Kinase Activation , 2000, The Journal of Neuroscience.

[4]  K. Sugahara,et al.  The role of acidic fibroblast growth factor in recovery of acoustic trauma , 2001, Neuroreport.

[5]  D. Henderson,et al.  Changes in cochlear antioxidant enzyme activity after sound conditioning and noise exposure in the chinchilla , 1998, Hearing Research.

[6]  P. Portincasa,et al.  Effect of dietary restriction and N-acetylcysteine supplementation on intestinal mucosa and liver mitochondrial redox status and function in aged rats , 2004, Experimental Gerontology.

[7]  J. Quadrilatero,et al.  N-Acetyl-L-cysteine prevents exercise-induced intestinal lymphocyte apoptosis by maintaining intracellular glutathione levels and reducing mitochondrial membrane depolarization. , 2004, Biochemical and biophysical research communications.

[8]  Y. Fujita,et al.  Antioxidant effects of stereoisomers of N-acetylcysteine (NAC), L-NAC and D-NAC, on angiotensin II-stimulated MAP kinase activation and vascular smooth muscle cell proliferation. , 2004, Journal of pharmacological sciences.

[9]  Jochen Schacht,et al.  Protection from noise-induced lipid peroxidation and hair cell loss in the cochlea , 2003, Brain Research.

[10]  J. Schacht,et al.  Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line-derived neurotrophic factor in vivo , 1999, Brain Research.

[11]  Linda McWilliams,et al.  Noise Exposure and Hearing Loss Among Sand and Gravel Miners , 2004, Journal of occupational and environmental hygiene.

[12]  The effectiveness of the Navy's Hearing Conservation Program. , 1995, Military medicine.

[13]  T. Horie,et al.  N‐acetylcysteine attenuates TNF‐α‐induced p38 MAP kinase activation and p38 MAP kinase‐mediated IL‐8 production by human pulmonary vascular endothelial cells , 2001, British journal of pharmacology.

[14]  Guang-di Chen,et al.  NMDA receptor blockage protects against permanent noise-induced hearing loss but not its potentiation by carbon monoxide , 2001, Hearing Research.

[15]  R. Riffenburgh,et al.  Enhancing Intrinsic Cochlear Stress Defenses to Reduce Noise‐Induced Hearing Loss , 2002 .

[16]  G. Weisz,et al.  Oral magnesium intake reduces permanent hearing loss induced by noise exposure. , 1994, American journal of otolaryngology.

[17]  J. Jones,et al.  Effects of N‐acetylcysteine on glutathione oxidation and fatigue during handgrip exercise , 2005, Muscle & nerve.

[18]  G. Richard Price,et al.  Predicting mechanical damage to the organ of Corti , 2007, Hearing Research.

[19]  Jiefu Zheng,et al.  Prevention of impulse noise-induced hearing loss with antioxidants , 2005, Acta oto-laryngologica.

[20]  D. Ding,et al.  Targeted Mutation of the Gene for Cellular Glutathione Peroxidase (Gpx1) Increases Noise-Induced Hearing Loss in Mice , 2000, Journal of the Association for Research in Otolaryngology.

[21]  Rena H. Glaser,et al.  Preventing Occupational Hearing Loss-A Practical Guide , 1997 .

[22]  T. Yamasoba,et al.  Ebselen prevents noise-induced excitotoxicity and temporary threshold shift , 2005, Neuroscience Letters.

[23]  O. Wiklund,et al.  N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. , 1996, Atherosclerosis.

[24]  Bo Hua Hu,et al.  The Role of Oxidative Stress in Noise-Induced Hearing Loss , 2005, Ear and hearing.

[25]  Lihua He,et al.  Effects of α-tocopherol on noise-induced hearing loss in guinea pigs , 2003, Hearing Research.

[26]  D. Robertson.  Functional significance of dendritic swelling after loud sounds in the guinea pig cochlea , 1983, Hearing Research.

[27]  Ó. Escribano,et al.  Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine , 2004, Journal of Pharmacology and Experimental Therapeutics.

[28]  J. Virkkala,et al.  Blockade of c-Jun N-terminal kinase pathway attenuates gentamicin-induced cochlear and vestibular hair cell death , 2002, Hearing Research.

[29]  B. Bohnker,et al.  U.S. Navy and Marine Corps Hearing Conservation Program, 1995-1999: mean hearing thresholds for enlisted personnel by gender and age groups. , 2002, Military Medicine.

[30]  A. Nuttall,et al.  Influence of intense sound exposure on glutathione synthesis in the cochlea , 1998, Brain Research.

[31]  Sun-Hee Kim,et al.  Preventive effect of antioxidants in MPTP-induced mouse model of Parkinson's disease , 2004, Neuroscience Letters.

[32]  F. de Ribaupierre,et al.  A Peptide Inhibitor of C-jun N-terminal Kinase Protects against Both Aminoglycoside and Acoustic Trauma-induced Auditory Hair Cell Death and Hearing Loss , 2022 .

[33]  M. Hoffer,et al.  A Radical Demise: Toxins and Trauma Share Common Pathways in Hair Cell Death , 1999, Annals of the New York Academy of Sciences.

[34]  B. Canlon.  The effect of acoustic trauma on the tectorial membrane, stereocilia, and hearing sensitivity: possible mechanisms underlying damage, recovery, and protection. , 1988, Scandinavian audiology. Supplementum.

[35]  E. Borg,et al.  Dose and time-dependent protection of the antioxidant N-l-acetylcysteine against impulse noise trauma , 2004, Hearing Research.

[36]  R Neitzel,et al.  Prospective noise induced changes to hearing among construction industry apprentices , 2005, Occupational and Environmental Medicine.

[37]  T. Yamashita,et al.  Direct inner ear infusion of dexamethasone attenuates noise-induced trauma in guinea pig , 2004, Hearing Research.

[38]  R. Kopke,et al.  Pharmacological rescue of noise induced hearing loss using N-acetylcysteine and acetyl-l-carnitine , 2007, Hearing Research.

[39]  J. Quevedo,et al.  Protective effect of N-acetylcysteine and deferoxamine on carbon tetrachloride-induced acute hepatic failure in rats , 2004, Critical care medicine.

[40]  H Ising,et al.  Reduction in noise-induced temporary threshold shift in humans following oral magnesium intake. , 2004, Clinical otolaryngology and allied sciences.

[41]  E. Neuwelt,et al.  The Chemoprotective Agent N-Acetylcysteine Blocks Cisplatin-Induced Apoptosis through Caspase Signaling Pathway , 2005, Journal of Pharmacology and Experimental Therapeutics.

[42]  K. Sugahara,et al.  The clinical free radical scavenger, edaravone, protects cochlear hair cells from acoustic trauma. , 2004, European journal of pharmacology.

[43]  Eric C. Bielefeld,et al.  Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration , 2007, Acta oto-laryngologica.

[44]  S. Kramer,et al.  Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music. , 2006, Journal of the American Academy of Audiology.

[45]  Jing Wang,et al.  Neuroprotective effect of riluzole in acute noise-induced hearing loss , 2005, Neuroreport.

[46]  Y. Suárez,et al.  AplidinTM Induces Apoptosis in Human Cancer Cells via Glutathione Depletion and Sustained Activation of the Epidermal Growth Factor Receptor, Src, JNK, and p38 MAPK* , 2003, The Journal of Biological Chemistry.

[47]  M. Di Paola,et al.  Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. , 2005, Free radical biology & medicine.

[48]  D. Ding,et al.  A comparison of changes in the stereocilia between temporary and permanent hearing losses in acoustic trauma , 1992, Hearing Research.

[49]  D. Lim,et al.  Anatomic correlates of noise induced hearing loss. , 1979, Otolaryngologic clinics of North America.

[50]  M. Liberman,et al.  Lateral Wall Histopathology and Endocochlear Potential in the Noise-Damaged Mouse Cochlea , 2003, Journal of the Association for Research in Otolaryngology.

[51]  W S Beckett,et al.  Hearing conservation for farmers: source apportionment of occupational and environmental factors contributing to hearing loss. , 2000, Journal of occupational and environmental medicine.

[52]  Bo Hua Hu,et al.  R-phenylisopropyladenosine attenuates noise-induced hearing loss in the chinchilla 1 Presented in part at the Midwinter Meeting of the Association for Research in Otolaryngology, 1997, St. Petersburg Beach, FL. 1 , 1997, Hearing Research.

[53]  T. Nicotera,et al.  Extremely rapid induction of outer hair cell apoptosis in the chinchilla cochlea following exposure to impulse noise , 2006, Hearing Research.

[54]  M. Seidman,et al.  Effects of Resveratrol on Acoustic Trauma , 2003, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[55]  S. De Flora,et al.  Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. , 2001, Carcinogenesis.

[56]  E. Cadenas,et al.  Mitochondrial oxidative stress: a self-propagating process with implications for signaling cascades. , 2000, BioFactors.

[57]  Thais C. Morata,et al.  Considerations on assessing the risk of work-related hearing loss. , 2001, Noise & health.

[58]  M. Liberman,et al.  Hair cell condition and auditory nerve response in normal and noise-damaged cochleas. , 1979, Acta oto-laryngologica.

[59]  D. Henderson,et al.  Prevention of noise-induced hearing loss with Src-PTK inhibitors , 2005, Hearing Research.

[60]  H. Erbaş,et al.  Effects of N-acetylcysteine on arginase, ornithine and nitric oxide in renal ischemia-reperfusion injury. , 2004, Pharmacological research.

[61]  P. Moldéus,et al.  Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems. , 1987, Biopharmaceutics & drug disposition.

[62]  Jochen Schacht,et al.  Glutathione limits noise-induced hearing loss , 2000, Hearing Research.

[63]  B. Halliwell,et al.  Free Radicals and Hearing: Cause, Consequence, and Criteria , 1999, Annals of the New York Academy of Sciences.

[64]  James S. Wright,et al.  Early Elevation of Cochlear Reactive Oxygen Species following Noise Exposure , 1999, Audiology and Neurotology.

[65]  J. Schacht,et al.  Calcineurin activation contributes to noise‐induced hearing loss , 2004, Journal of neuroscience research.

[66]  E. Lynch,et al.  Compounds for the prevention and treatment of noise-induced hearing loss. , 2005, Drug discovery today.

[67]  Noise exposures of rail workers at a North American chemical facility. , 2005, American journal of industrial medicine.

[68]  H. Chung,et al.  Induction of endothelial iNOS by 4-hydroxyhexenal through NF-κB activation , 2004 .

[69]  M. Seidman,et al.  Biologic activity of mitochondrial metabolites on aging and age-related hearing loss. , 2000, The American journal of otology.

[70]  D. Henderson,et al.  Anatomical effects of impact noise , 1994, Hearing Research.

[71]  H Yamane,et al.  The emergence of free radicals after acoustic trauma and strial blood flow. , 1995, Acta oto-laryngologica. Supplementum.

[72]  V. Sirot,et al.  Protective Effect of Carnosine on Excitable Structures of the Auditory Apparatus in Albino Rats with Acute Acoustic Trauma , 2004, Bulletin of Experimental Biology and Medicine.

[73]  Jean-Luc Puel,et al.  Excitotoxicity and repair of cochlear synapses after noise‐trauma induced hearing loss , 1998, Neuroreport.

[74]  T. Matsunobu,et al.  Acoustic trauma enhances DNA binding of transcription factor AP‐1 in the guinea pig inner ear , 2000, Neuroreport.

[75]  A. Nuttall,et al.  Upregulated iNOS and oxidative damage to the cochlear stria vascularis due to noise stress , 2003, Brain Research.

[76]  M. Ikeda,et al.  Oxidative neuronal death caused by glutamate uptake inhibition in cultured hippocampal neurons , 2003, Journal of neuroscience research.

[77]  Role of glutathione in protection against noise-induced hearing loss , 1998, Brain Research.

[78]  E. Neuwelt,et al.  Protection against Cisplatin-Induced Toxicities by N-Acetylcysteine and Sodium Thiosulfate as Assessed at the Molecular, Cellular, and in Vivo Levels , 2005, Journal of Pharmacology and Experimental Therapeutics.

[79]  Richard Neitzel,et al.  The Effectiveness of Hearing Protection Among Construction Workers , 2005, Journal of occupational and environmental hygiene.

[80]  D. Lim,et al.  Acoustic damage of the cochlea. A scanning and transmission electron microscopic observation. , 1971, Archives of otolaryngology.

[81]  Yan-min Zhang,et al.  [Changes in antioxidant capacity of the guinea pig exposed to noise and the protective effect of alpha-lipoic acid against acoustic trauma]. , 2003, Sheng li xue bao : [Acta physiologica Sinica].

[82]  S. P. Lund,et al.  Rats exposed to Toluene and Noise may develop Loss of Auditory Sensitivity due to Synergistic Interaction. , 2000, Noise & health.

[83]  T. Yamasoba,et al.  Glial cell line-derived neurotrophic factor has a dose dependent influence on noise-induced hearing loss in the guinea pig cochlea , 2000, Hearing Research.

[84]  W. Banks,et al.  Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12 , 2005, Brain Research.

[85]  B. Rumack,et al.  Clinical safety of high oral doses of acetylcysteine. , 1983, Seminars in oncology.

[86]  M. Seidman,et al.  The Protective Effects of Allopurinol and Superoxide Dismutase on Noise-Induced Cochlear Damage , 1993, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[87]  Jochen Schacht,et al.  Intense noise induces formation of vasoactive lipid peroxidation products in the cochlea , 2000, Brain Research.

[88]  T. Nicotera,et al.  Involvement of apoptosis in progression of cochlear lesion following exposure to intense noise 1 1 Presented in part at the Midwinter Meeting of the Association for Research in Otolaryngology, 2001, St. Petersburg Beach, FL, USA. , 2002, Hearing Research.

[89]  I. Cotgreave,et al.  N-acetylcysteine: pharmacological considerations and experimental and clinical applications. , 1997, Advances in pharmacology.

[90]  O. Aruoma,et al.  The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. , 1989, Free radical biology & medicine.

[91]  D Henderson,et al.  Impulse noise: critical review. , 1986, The Journal of the Acoustical Society of America.

[92]  M. Ahmad,et al.  Molecular mechanisms of N-acetylcysteine actions , 2003, Cellular and Molecular Life Sciences CMLS.

[93]  Shailendra Giri,et al.  Administration of N‐acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke , 2004, Journal of neuroscience research.

[94]  Kaoru Ogawa,et al.  Expression of c-Fos after noise-induced temporary threshold shift in the guinea pig cochlea , 2002, Neuroscience Letters.

[95]  J. Puel,et al.  Pathophysiology of the glutamatergic synapses in the cochlea. , 1993, Acta oto-laryngologica.

[96]  T. Nicotera,et al.  The Caspase Pathway in Noise-Induced Apoptosis of the Chinchilla Cochlea , 2003, Journal of the Association for Research in Otolaryngology.

[97]  W. Arnold,et al.  The effect of blood flow promoting drugs on cochlear blood flow, perilymphatic pO2 and auditory function in the normal and noise-damaged hypoxic and ischemic guinea pig inner ear , 2000, Hearing Research.

[98]  Jochen Schacht,et al.  Delayed production of free radicals following noise exposure , 2004, Brain Research.

[99]  E. Rubel,et al.  Mitochondrial role in hair cell survival after injury , 1995 .

[100]  Deborah Imel Nelson,et al.  The global burden of occupational noise-induced hearing loss. , 2005, American journal of industrial medicine.

[101]  Wei Ping Yang,et al.  Quantitative analysis of apoptotic and necrotic outer hair cells after exposure to different levels of continuous noise , 2004, Hearing Research.

[102]  M. Zaretsky,et al.  N‐acetylcysteine replenishes glutathione in HIV infection , 2000, European journal of clinical investigation.

[103]  T. Montine,et al.  Congeners of N(alpha)-acetyl-L-cysteine but not aminoguanidine act as neuroprotectants from the lipid peroxidation product 4-hydroxy-2-nonenal. , 2000, Free radical biology & medicine.

[104]  Young-Ho Chung,et al.  Effect of High-Dose Intravenous N-acetylcysteine on the Concentration of Plasma Sulfur-Containing Amino Acids , 2005, The Korean journal of internal medicine.

[105]  D Henderson,et al.  Biologic bases of noise-induced hearing loss. , 1995, Occupational medicine.

[106]  R. Salvi,et al.  Paraquat-Induced Hair Cell Damage and Protection with the Superoxide Dismutase Mimetic M40403 , 2004, Audiology and Neurotology.

[107]  G. Moonen,et al.  Oxidative stress-induced apoptosis of cochlear sensory cells: otoprotective strategies , 2000, International Journal of Developmental Neuroscience.