John K.M. Coleman

Enhancing Intrinsic Cochlear Stress Defenses to Reduce Noise-Induced Hearing Loss

Objectives/Hypothesis 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 N‐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.

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.

Prevention of impulse noise-induced hearing loss with antioxidants

Conclusion These findings indicate a strong protective effect of ALCAR and NAC on impulse noise-induced cochlear damage, and suggest the feasibility of using clinically available antioxidant compounds to protect the ear from acute acoustic injury. Objective Reactive oxygen species have been shown to play a significant role in noise-induced hearing loss. In the current study, the protective effects of two antioxidants, acetyl-L-carnitine (ALCAR) and N-L-acetylcysteine (NAC), were investigated in a chinchilla model of hearing loss resulting from impulse noise. It was hypothesized that pre- and post-treatment with these antioxidants would ameliorate the effects of impulse noise compared to saline-treated controls. Material and methods Eighteen animals were randomly assigned to 1 of 3 groups and exposed to impulse noise at a level of 155 dB peak SPL for 150 repetitions. ALCAR or NAC were administered twice daily (b.i.d.) for 2 days and 1 h prior to and 1 h following noise exposure, and then b.i.d. for the following 2 days. For the control group, saline was injected at the same time points. Auditory brainstem responses (ABRs) were recorded. Cochlear surface preparations were made to obtain cytocochleograms. Results Three weeks after exposure, permanent threshold shifts for the experimental groups were significantly reduced to ≈10–30 dB less than that for the control group (p<0.01). Less hair cell loss was also observed in the ALCAR and NAC groups than in the control group.

Pharmacological rescue of noise induced hearing loss using N-acetylcysteine and acetyl-L-carnitine.

Despite the use of hearing protection devices (HPDs) and engineering changes designed to improve workspaces, noise-induced hearing loss continues to be one of the most common and expensive disabilities in the US military. Many service members suffer acoustic trauma due to improper use of HPDs, sound levels exceeding the protective capacity of the HPDs, or by unexpected, injurious exposures. In these cases, there is no definitive treatment for the hearing loss. This study investigated the use of the pharmacological agents N-acetylcysteine and acetyl-L-carnitine after acoustic trauma to treat cochlear injury. N-Acetylcysteine is an antioxidant and acetyl-L-carnitine a compound that maintains mitochondrial bio-energy and integrity. N-Acetylcysteine and acetyl-L-carnitine, respectively, significantly reduced permanent threshold shifts and hair cell loss compared to saline-treated animals when given 1 and 4 h post-noise exposure. It may be possible to obtain a greater therapeutic effect using these agents in combination or at higher doses or for a longer period of time to address the secondary oxidative events occurring 7-10 days after acute noise exposure.

Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration

Conclusion. These studies extend previous work on N-acetyl-l-cysteine (NAC) and noise, showing protection with NAC against a high-kurtosis noise, showing protection with NAC at low doses, as well as protection by oral gavage. The studies further reveal the potential for the use of NAC in a clinical population exposed to noise. Objective. To extend previous work on NAC protection from noise, the current study examined the effectiveness of NAC against a high-kurtosis noise that combined continuous and impact noise, tested the effectiveness of NAC at varying doses, and tested NAC when administered by gavage. Materials and methods. Chinchillas were tested for auditory brainstem responses (ABRs) at five frequencies before and at three time points after one of three noise exposures: high-kurtosis (2 h, 108 dB Leq), impulse (75 pairs of 155 dB pSPL impulses), or continuous (4 kHz octave band, 105 dB SPL for 6 h). Animals were treated with NAC or saline vehicle before and after noise. Results. The NAC was protective against the high-kurtosis noise both at low doses and when given orally by gavage.

AM-111 protects against permanent hearing loss from impulse noise trauma.

The otoprotective peptide AM-111, a cell-permeable inhibitor of JNK mediated apoptosis, was tested for its efficacy as a rescue agent following impulse noise trauma. Single dose administrations of AM-111 at 1h or 4h post-impulse noise exposure (155 dB peak SPL) via systemic or local routes were evaluated with a total of 48 chinchillas. The animals received the compound either by IP injection or locally onto the round window membrane (hyaluronic acid gel formulation or osmotic mini-pump). Efficacy was determined by auditory brainstem responses (ABR) as well as cytocochleograms. Three weeks after impulse noise exposure, permanent threshold shifts (PTS) were significantly lower for AM-111 treated ears compared to controls, regardless of the drug administration route and the time point of drug delivery. Even the treatments which started 4h post-noise exposure, reduced hearing loss in the 2-8 kHz range compared to controls by up to 16-25 dB to a PTS as low as 6-17 dB, demonstrating significant protection against permanent hearing loss from impulse noise trauma. These findings suggest a key role for JNK mediated cochlear sensory cell death from oxidative stress.

Low-Dose D-Methionine and N-Acetyl-L- Cysteine for Protection from Permanent Noise-Induced Hearing Loss in Chinchillas

Objective. Despite efforts at public health awareness and stringent industrial standards for hearing protection, noise-induced hearing loss (NIHL) remains a formidable public health concern. Although many antioxidants have proven to be beneficial in the laboratory for prevention of permanent NIHL, low-dose combinations of compounds with different biochemical mechanisms of action may allow long-term administration with fewer side effects and equal efficacy. The mixture of D-methionine and N-acetyl-L-cysteine administered at levels less than 10% of standard dosing has not been previously reported. Study Design. Twenty-six female adult Chinchilla laniger were placed in 4 study groups, consisting of (1) a group receiving combination 12.5 mg/kg each D-methionine and N-acetyl-L-cysteine (DMET/NAC group), (2) a group receiving 12.5 mg/kg D-methionine (DMET-only group), (3) a group receiving 12.5 mg/kg N-acetyl-L-cysteine (NAC-only group), and (4) saline controls. Setting. Laboratory. Subjects and Methods. All groups received twice-daily intraperitoneal injections 2 days prior to noise exposure, 1 hour before and after exposure on day 3, and for 2 days subsequently, totaling 10 doses of 125 mg/kg for each antioxidant over 5 days. Results. Although NAC-only animals paralleled saline control recovery during 3 weeks, the DMET-only group revealed gradual improvement with statistically significant recovery in the middle frequencies. The DMET/NAC group showed significant improvement at most frequencies compared with controls (P < .001 and P < .05). Conclusion. Significant recovery of hearing was observed following continuous noise exposure with either DMET only or a combination of low-dose DMET/NAC, demonstrating a considerably lower dose of antioxidants required than previously reported for hearing recovery following acoustic trauma.

Pressure sensors for printed blast dosimeters

Disposable printed sensor tapes are being developed to record the magnitude of explosive blasts in the battlefield. The goal is to detect and mitigate the possible occurrence of traumatic brain injury in soldiers. This paper presents results on the pressure sensors to measure the blast pressure and the blast noise. The sensors are based on piezoelectric polymers and their fabrication is compatible with roll-to-roll fabrication methods to enable low cost.

09:50: Prevention of Synaptic Edema by Noise Exposure in Chinchilla

through transplantation of stem cells are ongoing, though optimization of these techniques has not been achieved. In particular, there is a lack of understanding of what makes a particular cochlear microenvironment more suitable for successful transplantation. The present study was designed to examine changes in expression patterns of various trophic factors following chemical-induced cochlear injury in an effort to optimize cell transplantation techniques. METHODS: Stem cell survival has been noted in both “acuteinjury” (1-3 days after ouabain exposure) and “chronic-injury” (7 days or longer) cochleas, though a greater number of surviving cells are seen in the acute-injury group. In the present study, ouabain was applied to the round window niche of mice. The animals recovered for 24 hours to several days and the cochleas were harvested. The tissue was subjected to real time RT-PCR using primers for various trophic factors. Comparisons between control and treatment cochleas were performed while protein assays of ouabain-treated cochleas were also performed. RESULTS: Examination of ouabain-treated cochleas revealed differential expression patterns of both mRNA and protein for various trophic factors (VEGF, GFAP, MMP) as compared with control cochleas. In particular, real time RT-PCR analysis revealed a several-fold increase in MMP mRNA levels in acute-injury cochleas. Moreover, differences in expression patterns were also noted depending upon the duration of recovery after ouabain exposure. CONCLUSION: In the present study, several differences in expression patterns of various trophic factors were identified following injury with ouabain. In particular, MMP, a protein important in vasculogenesis, was found to be increased several-fold (mRNA levels) in the acute-injury cochleas. SIGNIFICANCE: An understanding of the cochlear microenvironment will be necessary for further growth in the area of cell transplantation. It is hoped that new treatments will be developed to help those with sensorineural hearing loss. SUPPORT: NIHDC7506 Resident Research Committee Grant, Medical University of South Carolina.