Cochlear Oxidative Stress Research Articles

Effects of Apelin-13 on auditory system in STZ-induced diabetic rats

AimDamage to the auditory pathways is one of the complications of diabetes. The aim of this study was to investigate the potential therapeutic effects of apelin-13 in the auditory pathways of rats with experimentally induced diabetes by examining its effect on auditory brainstem responses, cochlear oxidative stress and inflammatory cytokines. MethodsThirty-two male Wistar albino rats were divided into four groups: sham control, diabetes, apelin and diabetes + apelin. A single dose of 45 mg/kg streptozotocin (STZ) was administered to induce diabetes. The apelin group received 50 µg/kg apelin-13 for seven days intraperitoneally (ip). At the end of the apelin and STZ applications auditory brainstem responses (ABR) was recorded. At the end of the experiment, cochlea was removed and biochemical analyzes were performed. ResultsIn ABR recordings, the latencies of wave V in diabetic group were observed to be longer than those of the control, with the apelin treatment exhibiting a partial reversal of this situation, particularly at specific frequencies and intensity levels. Apelin treatment leads to a significant increase in total antioxidant status (TAS) and a reduction in total oxidant status (TOS) and oxidative stress index (OSI) in cochlea compared to diabetic groups. The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1 beta) in cochlear tissue were found to be significantly reduced in the apelin-treated group compared to the diabetic group. ConclusionApelin-13 may have a protective effect on the auditory system and may be proposed as a potential new therapeutic strategy for the management diabetic auditory impairment.

2D Catalytic Niobium Carbide MXenzyme for Ameliorating Noise‐Induced Hearing Loss

AbstractNoise‐induced hearing loss (NIHL), a prevalent sensory disability affecting a majority of the global population, is dominantly induced by mitochondrial dysfunction and oxidative stress, but no effective therapeutic strategy is available. Herein, the potential of a 2D catalytic niobium carbide (Nb2C) MXenzyme is investigated as a nanomedicine for treating NIHL by scavenging reactive oxygen species (ROS). The findings reveal that 2D Nb2C MXenzyme effectively eliminates free radicals, resulting in a substantial reduction of ROS in House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells treated with hydrogen peroxide (H2O2). Additionally, the 2D Nb2C MXenzyme demonstrates significant protection on hair cells by preventing cytotoxicity and apoptosis induced by H2O2. In vivo experiments further support the efficacy of the 2D Nb2C MXenzyme in restoring hearing impairment caused by extensive noise exposure. Specifically, it restores the raised amplitude of Wave I in auditory brainstem response (ABR) records and promotes the recovery of damaged ribbon synapses in inner hair cells. Notably, the therapeutic effect of the 2D Nb2C MXenzyme is attributed to its ability to suppress cochlear oxidative stress evidenced by immunohistochemical analysis. This research provides a new approach for treating hearing loss‐related ear diseases by utilizing catalytic biomaterials and nanomedicine with enzyme‐mimicking properties.

L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25–26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing – Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Mito-TEMPO Attenuates Oxidative Stress and Mitochondrial Dysfunction in Noise-Induced Hearing Loss via Maintaining TFAM-mtDNA Interaction and Mitochondrial Biogenesis.

The excessive generation of reactive oxygen species (ROS) and mitochondrial damage have been widely reported in noise-induced hearing loss (NIHL). However, the specific mechanism of noise-induced mitochondrial damage remains largely unclear. In this study, we showed that acoustic trauma caused oxidative damage to mitochondrial DNA (mtDNA), leading to the reduction of mtDNA content, mitochondrial gene expression and ATP level in rat cochleae. The expression level and mtDNA-binding function of mitochondrial transcription factor A (TFAM) were impaired following acoustic trauma without affecting the upstream PGC-1α and NRF-1. The mitochondria-target antioxidant mito-TEMPO (MT) was demonstrated to enter the inner ear after the systemic administration. MT treatment significantly alleviated noise-induced auditory threshold shifts 3d and 14d after noise exposure. Furthermore, MT significantly reduced outer hair cell (OHC) loss, cochlear ribbon synapse loss, and auditory nerve fiber (ANF) degeneration after the noise exposure. In addition, we found that MT treatment effectively attenuated noise-induced cochlear oxidative stress and mtDNA damage, as indicated by DHE, 4-HNE, and 8-OHdG. MT treatment also improved mitochondrial biogenesis, ATP generation, and TFAM-mtDNA interaction in the cochlea. These findings suggest that MT has protective effects against NIHL via maintaining TFAM-mtDNA interaction and mitochondrial biogenesis based on its ROS scavenging capacity.

Effect of Ischemia-Induced Cochlear Inflammation on Auditory Responses in Male Rats

Background and Aim: Ischemic injury is a major cause of hearing loss and oxidative stress is an important part of ischemic injury. The goal of this study was to evaluate the cochlear oxidative stress effect on auditory responses in male rats. Methods: Cochlear oxidative stress was induced by bilateral carotid artery occlusion for 20 minutes. The rats were evaluated by biochemical inflammatory factors tumor necrosis factor-α [TNF-α] and C-reactive protein (CRP) in the day before and 1st, 4th, and 7th days following surgery. The auditory brainstem response (ABR) and electrocochleography (ECochG) were evaluated on the day before surgery and 14th, 21th and 28th days after surgery. Results: TNF-α and CRP levels concentrations increased one day after ischemia and subsequently decreased on the 7th day. The click and tone burst evoked ABR showed increased thresholds on day14th, 21th, and 28th. The highest threshold was recorded on day14th. The ECochG results also were abnormal for 55%, 70%, and 45% of cases on day 14th, 21th, and 28th, respectively. Conclusion: Cochlear oxidative stress affects hearing sensitivity. The ABR shows elevated thresholds and abnormal ECochG was found in many cases.

Bilateral Carotid Artery Occlusion and Cochlear Oxidative Stress and Hearing Loss in Rats.

Introduction:This study aimed to evaluate the effects of bilateral carotid artery occlusion on cochlear oxidative stress and hearing status in rats.Methods:The rats were divided into two sets. The first set was used for electrophysiological recording (click and 4 kHz tone burst auditory brainstem responses and electrocochleography) on the day before surgery and then on the first, fourth, and seventh days after surgery. Animals of the second set were used for biochemical analysis. The cochlea of animals in the second set was collected on the first, fourth, and seventh days after carotids occlusion for biochemical analysis. For the control groups, no carotids occlusion was done. For ischemia induction, both common carotid arteries were occluded for 20 minutes.Results:Electrophysiological analysis showed that burst auditory brainstem thresholds significantly elevated after common carotid arteries occlusion on the first, fourth, and seventh days after surgery with abnormal electrocochleography results at 75%, 70%, and 85% on the first, fourth, and seventh days after surgery, respectively. The electrophysiological finding confirmed by biochemical results that showed malondialdehyde and nitric oxide levels increased and superoxide dismutase and catalase activities decreased after occlusion in cochlea tissue.Conclusion:This study showed that bilateral common carotid artery occlusion increases cochlear oxidative stress and induces hearing loss in rats.

Novel QUEST MRI In Vivo Measurement of Noise-induced Oxidative Stress in the Cochlea

Effective personalized therapeutic treatment for hearing loss is currently not available. Cochlear oxidative stress is commonly identified in the pathogenesis of hearing loss based upon findings from excised tissue, thus suggesting a promising druggable etiology. However, the timing and site(s) to target for anti-oxidant treatment in vivo are not clear. Here, we address this long-standing problem with QUEnch-assiSTed Magnetic Resonance Imaging (QUEST MRI), which non-invasively measures excessive production of free radicals without an exogenous contrast agent. QUEST MRI is hypothesized to be sensitive to noise-evoked cochlear oxidative stress in vivo. Rats exposed to a loud noise event that resulted in hair cell loss and reduced hearing capability had a supra-normal MRI R1 value in their cochleae that could be corrected with anti-oxidants, thus non-invasively indicating cochlear oxidative stress. A gold-standard oxidative damage biomarker [heme oxidase 1 (HO-1)] supported the QUEST MRI result. The results from this study highlight QUEST MRI as a potentially transformative measurement of cochlear oxidative stress in vivo that can be used as a biomarker for improving individual evaluation of anti-oxidant treatment efficacy in currently incurable oxidative stress-based forms of hearing loss.

Chronic lead exposure induces cochlear oxidative stress and potentiates noise-induced hearing loss

Acquired hearing loss is caused by complex interactions of multiple environmental risk factors, such as elevated levels of lead and noise, which are prevalent in urban communities. This study delineates the mechanism underlying lead-induced auditory dysfunction and its potential interaction with noise exposure. Young-adult C57BL/6 mice were exposed to: 1) control conditions; 2) 2 mM lead acetate in drinking water for 28 days; 3) 90 dB broadband noise 2 h/day for two weeks; and 4) both lead and noise. Blood lead levels were measured by inductively coupled plasma mass spectrometry analysis (ICP-MS) lead-induced cochlear oxidative stress signaling was assessed using targeted gene arrays, and the hearing thresholds were assessed by recording auditory brainstem responses. Chronic lead exposure downregulated cochlear Sod1, Gpx1, and Gstk1, which encode critical antioxidant enzymes, and upregulated ApoE, Hspa1a, Ercc2, Prnp, Ccl5, and Sqstm1, which are indicative of cellular apoptosis. Isolated exposure to lead or noise induced 8–12 dB and 11–25 dB shifts in hearing thresholds, respectively. Combined exposure induced 18–30 dB shifts, which was significantly higher than that observed with isolated exposures. This study suggests that chronic exposure to lead induces cochlear oxidative stress and potentiates noise-induced hearing impairment, possibly through parallel pathways.

The Antioxidant Effect of Rosmarinic Acid by Different Delivery Routes in the Animal Model of Noise-Induced Hearing Loss.

Trans-tympanic Rosmarinic Acid (RA), as compared with the systemic administration, protects against noise-induced auditory hair cell and hearing losses in rats in vivo. ROS production, lipoperoxidative damage, and an imbalance of antioxidant defences play a significant role in noise-induced hearing loss. Several molecules with antioxidant properties have been tested to restore redox homeostasis; however, drug delivery system represents a challenge for their effectiveness. In our model, acute and intense noise exposure induces hearing loss, hair cell death, and oxidative stress, with an increase in superoxide production and over-expression of lipid peroxidation in cochlear structures. RA was administrated in male Wistar rats by trans-tympanic (20 μl) and systemic (10 mg/kg) modality. In systemic administration, RA was injected 1 hour before noise exposure and once daily for the following 3 days. ABRs were measured before and at days 1, 3, 7, and 30 after noise exposure. Rhodamine-phalloidin staining, dihydroethidium and 8-isoprostane immunostainings were performed to assess and quantify outer hair cells loss, superoxide production, and lipid peroxidation in the different experimental groups. Systemic RA administration significantly decreased noise-induced hearing loss and the improvement of auditory function was paralleled by a significant reduction in cochlear oxidative stress. The trans-tympanic modality of drug administration showed a similar degree of protection both at the functional and morphological levels. The effectiveness of RA given via trans-tympanic injection could be interesting for the future application of this minimally-invasive procedure in the treatment of ROS-induced hearing loss.

92 - Chronic Lead Exposure Induces Cochlear Oxidative Stress and Impairs Hearing

Oxidative stress plays a pivotal role in mediating hearing loss induced by exposure to a number of environmental risk factors. Elevated levels of lead is one of the commonly encountered risk factor in the urban environment. Though lead exposure damages the sensory, vascular, and neuronal components of the cochlea, it is not known whether oxidative stress mediates its ototoxic effects. The aim of this study is to delineate the redox mechanism underlying lead-induced auditory dysfunction. Young-adult C57BL/6 mice were exposed to: 1) control conditions or 2) 2 mM lead acetate in drinking water for 28 days. Blood lead levels were measured by inductively coupled plasma mass spectrometry analysis (ICP-MS), lead-induced cochlear oxidative stress was assessed using targeted gene arrays, and hearing thresholds were assessed by recording auditory brainstem responses. Lead exposure significantly increased the blood lead levels to 293 ± 67 ppb. However, the body weight, appearance, and behavior of the lead-exposed mice were similar to that of the controls. This suggested that the exposure level was probably moderate for young-adult mice, and was not capable of inducing severe toxic effects. Nevertheless, lead exposure at this level downregulated cochlear Sod1, Gpx1, and Gstk1, which encode critical antioxidant enzymes, and upregulated ApoE, Hspa1a, Ercc2, Prnp, Ccl5, and Sqstm1, which are indicative of cellular apoptosis. In addition, exposure to lead induced 8-12 dB shifts in hearing thresholds. Collectively, these findings suggest that chronic exposure to even moderate levels of lead induces cochlear oxidative stress and causes hearing loss.

Rosmarinic acid up-regulates the noise-activated Nrf2/HO-1 pathway and protects against noise-induced injury in rat cochlea

Noise-induced hearing loss depends on progressive increase of reactive oxygen species and lipoperoxidative damage in conjunction with the imbalance of antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in the regulation of cellular defenses against oxidative stress, including heme oxygenase-1 (HO-1) activation. In this work we describe a link between cochlear oxidative stress damage, induced by noise exposure, and the activation of the Nrf2/HO-1 pathway. In our model, noise induces superoxide production and overexpression of the lipid peroxidation marker 4-hydroxy-nonenals (4-HNE). To face the oxidative stress, the endogenous defense system is activated as well, as shown by the slight activation of superoxide dismutases (SODs). In addition, we observed the activation of the Nrf2/HO-1 pathway after noise exposure. Nrf2 appears to promote the maintenance of cellular homeostasis under stress conditions. However, in this model the endogenous antioxidant system fails to counteract noise-induced cell damage and its activation is not effective enough in preventing cochlear damage. The herb-derived phenol rosmarinic acid (RA) attenuates noise-induced hearing loss, reducing threshold shift, and promotes hair cell survival. In fact, RA enhances the endogenous antioxidant defenses, as shown by decreased superoxide production, reduced expression of 4-HNE, and up-regulation of SODs. Interestingly, RA potentiates the Nrf2/HO-1 signaling pathway, as shown by immunohistochemical and Western blot analyses. Thus, protective effects of RA are associated with the induction/activation of the Nrf2-ARE signaling pathway in addition to RA direct scavenging capability.

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism.

Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n = 65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive-apoptotic cochlear cells. RT-quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase-complex adaptor cytochrome b-245, α-polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress.

Targeted Amelioration of Cisplatin‐Induced Ototoxicity

Objectives: Determine if local intratympanic (IT) administration of N-acetylcysteine (LNAC) improves cochlear glutathione levels versus systemic LNAC intraperitoneal (IP) administration, as indicated by decreased oxidized (GSSG)/reduced (GSH) glutathione ratios. Cisplatin is a platinum based ototoxic chemotherapeutic agent that induces injury secondary to the accumulation of reactive oxygen species. This pilot study assesses if different LNAC formulations or modes of administration decrease cochlear oxidative stress (GSSG/GSH ratio). Methods: Cisplatin was administered subcutaneously for 3 days (5.5 mg/kg SC/day x 3). Single LNAC formulations were administered to guinea pigs either via IT (solution), IT (nanocapsular gel), or IP (250mg/kg) 2 hours prior to Day 1 cisplatin dosing. On Day 3, cochlear tissue was microdissected, flash frozen, stored -70ºC, and assayed within 21 days. The levels of GSSG and GSH in homogenized cochlear tissue supernatants were determined in white half area 96-well plates (Corning) by assay kits (Promega) via luminometry (Dynex) and referenced per total protein (BCA assay, Pierce). Results: The greatest reduction in cisplatin induced GSSG/GSH occurred for LNAC 250 mg/kg IP pretreated animals, compared to the IT formulations and cisplatin only control groups. Conclusions: The greatest decrease of cochlear oxidative stress was seen when L-NAC was delivered IP prior to cisplatin treatment. Further studies are needed to determine the effects on hearing thresholds and the utility of this proposed cisplatin protective treatment.

Expression pattern of oxidative stress and antioxidant defense-related genes in the aging Fischer 344/NHsd rat cochlea

The biological mechanisms that give rise to age-related hearing loss (ARHL) are still poorly understood. However, there is growing recognition that oxidative stress may be an important factor. To address this issue, we measured the changes in the expression of cochlear oxidative stress and antioxidant defense-related genes in young (2 months old), middle-aged (12 months old), and old (21–25 months old) Fischer 344/NHsd (F344/NHsd) rats and compared gene expression changes with ARHL. A quantitative real-time reverse transcription polymerase chain reaction array revealed a significant age-related downregulation of only 1 gene, stearoyl-coenzyme A desaturase 1, and upregulation of 12 genes: 24-dehydrocholesterol reductase; aminoadipate-semialdehyde synthase; cytoglobin; dual oxidase 2; glutathione peroxidase 3; glutathione peroxidase 6; glutathione S-transferase, kappa 1; glutathione reductase; nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase, quinone 1; solute carrier Family 38, Member 5; thioredoxin interacting protein; and vimentin. Statistical analyses revealed significant correlations between gene expression and auditory function in 8 genes. Our results identified specific subsets of oxidative stress genes that appear to play an important role in ARHL in the Fischer 344/NHsd rat.

Effect of water-soluble coenzyme Q10 on noise-induced hearing loss in guinea pigs

Conclusion. The results of this study indicate that coenzyme Q10 reduces cochlear oxidative stress induced by acoustic overstimulation. Objective. We investigated the effects of coenzyme Q10 on noise-induced hearing loss in guinea pigs. Materials and methods. Animals received water-soluble coenzyme Q10 intraperitoneally 2 h before noise exposure. Seven days after noise exposure (130 dB sound pressure level for 3 h), the auditory brainstem response (ABR) threshold shift and cochlear hair cell damage were assessed. Results. We observed that the ABR threshold shift was significantly less in the coenzyme Q10 group than in the vehicle control group. In addition, the percentage of missing outer hair cells was lower in the coenzyme Q10 group than in the control group. Moreover, 2 days after administration of coenzyme Q10, increased antioxidative activity in the cochlea, as measured by analysis of hydroxy radical scavenging activity by electron spin resonance was observed.

Candidate's thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss.

Oxidative stress plays a substantial role in the genesis of noise-induced cochlear injury that causes permanent hearing loss. We present the results of three different approaches to enhance intrinsic cochlear defense mechanisms against oxidative stress. This article explores, through the following set of hypotheses, some of the postulated causes of noise-induced cochlear oxidative stress (NICOS) and how noise-induced cochlear damage may be reduced pharmacologically. 1) NICOS is in part related to defects in mitochondrial bioenergetics and biogenesis. Therefore, NICOS can be reduced by acetyl-L carnitine (ALCAR), an endogenous mitochondrial membrane compound that helps maintain mitochondrial bioenergetics and biogenesis in the face of oxidative stress. 2) A contributing factor in NICOS injury is glutamate excitotoxicity, which can be reduced by antagonizing the action of cochlear -methyl-D-aspartate (NMDA) receptors using carbamathione, which acts as a glutamate antagonist. 3) Noise-induced hearing loss (NIHL) may be characterized as a cochlear-reduced glutathione (GSH) deficiency state; therefore, strategies to enhance cochlear GSH levels may reduce noise-induced cochlear injury. The objective of this study was to document the reduction in noise-induced hearing and hair cell loss, following application of ALCAR, carbamathione, and a GSH repletion drug D-methionine (MET), to a model of noise-induced hearing loss. This was a prospective, blinded observer study using the above-listed agents as modulators of the noise-induced cochlear injury response in the species chinchilla langier. Adult chinchilla langier had baseline-hearing thresholds determined by auditory brainstem response (ABR) recording. The animals then received injections of saline or saline plus active experimental compound starting before and continuing after a 6-hour 105 dB SPL continuous 4-kHz octave band noise exposure. ABRs were obtained immediately after noise exposure and weekly for 3 weeks. After euthanization, cochlear hair cell counts were obtained and analyzed. RESULTS ALCAR administration reduced noise-induced threshold shifts. Three weeks after noise exposure, no threshold shift at 2 to 4 kHz and <10 dB threshold shifts were seen at 6 to 8 kHz in ALCAR-treated animals compared with 30 to 35 dB in control animals. ALCAR treatment reduced both inner and outer hair cell loss. OHC loss averaged <10% for the 4- to 10-kHz region in ALCAR-treated animals and 60% in saline-injected-noise-exposed control animals. Noise-induced threshold shifts were also reduced in carbamathione-treated animals. At 3 weeks, threshold shifts averaged 15 dB or less at all frequencies in treated animals and 30 to 35 dB in control animals. Averaged OHC losses were 30% to 40% in carbamathione-treated animals and 60% in control animals. IHC losses were 5% in the 4- to 10-kHz region in treated animals and 10% to 20% in control animals. MET administration reduced noise-induced threshold shifts. ANOVA revealed a significant difference (P <.001). Mean OHC and IHC losses were also significantly reduced (P <.001). These data lend further support to the growing body of evidence that oxidative stress, generated in part by glutamate excitotoxicity, impaired mitochondrial function and GSH depletion causes cochlear injury induced by noise. Enhancing the cellular oxidative stress defense pathways in the cochlea eliminates noise-induced cochlear injury. The data also suggest strategies for therapeutic intervention to reduce NIHL clinically.