Research paperNAC for noise: From the bench top to the clinic∗
Introduction
The most common potentially preventable form of sensorineural hearing impairment is noise-induced hearing loss (NIHL) from acute and/or chronic acoustic overexposure. Thirty to forty million workers in the US are at risk for NIHL due to noise exposure on the job, and NIHL contributes to the hearing loss of an estimated ten million Americans (Franks et al., 1996). It is estimated that 16% of disabling hearing loss in adults worldwide is due to occupational noise (Nelson et al., 2005). The military is one of the world’s most noise hazardous occupations, and NIHL in the military continues to be an acute and costly problem despite hearing conservation programs emphasizing personal hearing protection devices (HPDs) (Bohnker et al., 2002, Wolgemuth et al., 1995). Hearing damage from acoustic trauma accounts for up to 47% of all wounded in action evacuations from Operation Iraqi Freedom and Operation Enduring Freedom and is the fourth leading reason for medical referral for combatants returning from deployment. These injuries result in costly VA disability expenditures that are rising each year (Kopke, 2005). However, a variety of other occupations are also associated with significant acoustic overexposure including, manufacturing (Landen et al., 2004), transportation (Beckett et al., 2000, Landen et al., 2004, Landon et al., 2005), construction (Neitzel and Seixas, 2005, Seixas et al., 2005), mining (Landen et al., 2004), and others.
Hearing protection devices are an essential and partially effective part of any hearing conservation program but, due to their limitations, NIHL can still occur. These limitations include: (a) noise levels can exceed the protective capability of the device; (b) injurious acoustic energy can directly be transmitted through the skull bypassing the protective device to damage the cochlea; (c) HPD attenuation is frequency dependent; (d) their protective capability is reliant on precise fitting of the device, which under some conditions cannot always be maintained; (e) often the overriding need to communicate precludes wearing an HPD (Kopke et al., 2002). For example, long haul truck drivers are exposed to constant high level noise for many hours a week yet cannot wear HPD because of the need to hear critical environmental cues, and finally (f) damaging noise cannot always be anticipated, and short unexpected high intensity exposures can too frequently cause permanent damage (Price, 2005). Thus, while HPD compliance is always an issue, the aforementioned factors require additional solutions to improve hearing conservation effectiveness.
More than a decade ago, it was found that NIHL was not just mechanical or physical in nature, but that cochlear injury was also metabolically induced (Lim et al., 1971, Lim and Dunn, 1979, Slepecky, 1986). Since the discovery that noise-induced metabolic oxidative stress plays a significant role in acoustically-generated cochlear injury (Yamane et al., 1995), research has defined a variety of potential therapeutics effective in reducing the permanent hearing loss associated with acoustic overexposure in animal models (Kopke et al., 1999, Lynch and Kil, 2005). The success of a number of compounds in preventing hearing loss suggests other strategies for hearing conservation, namely, making the cochlea more resistant to acoustic injury or treating the acutely-injured cochlea through pharmacologic intervention.
The ideal pharmacologic agent would specifically address known mechanisms of acoustic injury, be orally administered, be exceptionally safe, be effective and affordable. This review looks at the accumulated data on one such agent, N-acetylcysteine (NAC), currently in clinical trials as an agent to prevent or treat acute acoustic trauma (AAT). NAC has been in clinical use with U.S. Food and Drug Administration (FDA) approval for several decades as an antidote to acetaminophen overdose and as a mucolytic agent (Miller and Rumack, 1983). At the present time, it is not FDA approved for any uses related to hearing loss.
NAC functions as an antioxidant and as a substrate for glutathione synthesis and has a number of other bioeffects as well (Zafarullah et al., 2003). A number of laboratories have demonstrated in various species and models of noise damage to hearing that NAC can effectively attenuate permanent hearing loss due to AAT. Thus NAC is postulated to effectively reduce NIHL by addressing many of the recently-discovered cellular and molecular mechanisms thought to be responsible for cochlear damage due to loud noise.
Section snippets
Cellular and molecular mechanisms associated with acoustic injury to the cochlea
Over the past decade it has become clear that oxidative stress induced by acoustic overexposure in excess of the cochlea’s intrinsic antioxidant stress defenses leads to cell injury, sensory cell death, and permanent hearing loss (Henderson et al., 2006). While acoustic overexposure can certainly be excessive enough to mechanically disrupt the cochlea resulting in a devastating and immediate unrecoverable injury, the clinical scenario is usually much less dramatic. Rather than macro-mechanical
How NAC may address many of the mechanisms associated with cochlear injury from AAT
As previously described, AAT appears to damage the cochlea through the generation of ROS, RNS, lipid peroxides and depletion of cochlear GSH and other cellular antioxidants. Without intrinsic antioxidant protection mitochondrial injury occurs and DNA and proteins are oxidatively damaged. A variety of programmed cell death pathways (CDPs) can be activated or necrosis can also be initiated (Hu et al., 2002, Hu et al., 2000, Yang et al., 2004). CDPs reported to be activated by acoustic trauma
NAC and acute steady state noise
Early publications suggested that cochlear antioxidant enzymes, including those involving GSH synthesis and utilization, were modulated with both conditioning and damaging steady state noise exposure (Jacono et al., 1998). Topical application to the cochlear round window membrane of an adenosine antagonist that was shown to up-regulate the activity of cochlear antioxidant enzymes also conferred protection from cochlear injury in chinchilla exposed to steady state noise (Hu et al., 1997).
NAC and acute impulse and kurtotic noise
Damaging noise may often be impulse (Henderson and Hamernik, 1986), impact (Henderson et al., 1994), or complex kurtotic noise (Henderson et al., 2001). The type of noise causing the injury may be a very important consideration. For example, intense impulse noise has been shown to cause a very rapid onset of outer hair cell apoptotic changes that may differ from steady state noise (Hu et al., 2006). To assess the effectiveness of NAC for impulse noise, chinchilla were exposed to 150 pairs of
NAC safety
NAC, a thiol-containing amino acid derivative, is used in the United States as a nutritional supplement and also a drug which has passed the stringent safety requirements for Food and Drug Administration (FDA) approval for prescription use only. Most of the abundant safety data for oral NAC is provided by its use in acetaminophen intoxication. In 1985, oral NAC emerged as the FDA-approved gold standard for safe and efficacious treatment/prevention of hepatic damage as a result of acute
NAC and early clinical data
To date several preliminary clinical trials have either been completed or initiated looking at the safety and efficacy of NAC in reducing noise-induced auditory changes. One study examined effects of oral NAC administration in ameliorating noise-induced temporary shifts. Another study investigating the safety and efficacy of NAC in preventing permanent noise-induced threshold shifts has completed subject recruitment and data collection and is in the process of preparation for publication. An
Summary
Acute acoustic trauma and NIHL are still very prevalent threats to hearing health despite continued deployment of hearing conservation programs. New and accumulating data regarding the role of oxidative stress and cochlear cell death in the pathogenesis of cochlear injury are providing a rational mechanism-based approach for preventing and treating noise-induced hearing loss with pharmacologic agents.
Acoustic overexposure leads to ischemia reperfusion, excessive glutamate release,
Acknowledgements
This work was supported by funding from the Office of Naval Research. The authors thank the staff of the Vivarium of the Naval Medical Center San Diego for their excellent support with animal care.
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