Research paperMechanisms of noise-induced hearing loss indicate multiple methods of prevention
Introduction
The significant clinical issue presented by noise-induced hearing loss (NIHL) has driven an effort to understand the underlying molecular and biochemical mechanisms of cell death in the cochlea, and to develop interventions to reduce or prevent NIHL. One major advance came with the knowledge that intense metabolic activity alters cellular redox state and drives the formation of free radicals (for reviews, see Halliwell and Gutteridge, 1998, Evans and Halliwell, 1999). Free radicals, which contain one or more unpaired electrons (see Halliwell and Gutteridge, 1998), include reactive oxygen species (ROS) and reactive nitrogen species (RNS). As a group, ROS/RNS are short-lived, unstable, highly reactive clusters of atoms. They are essential for cellular life processes; however, in excess they damage cellular lipids, proteins, and DNA, and upregulate apoptotic pathways (for a helpful summary of oxidative mechanisms, see Campbell, 2003). Better understanding of these key molecules has helped define interventions that significantly reduce NIHL and other environmentally mediated hearing impairments (such as aminoglycoside antibiotics and chemotherapeutics). In this review, we describe mechanisms of NIHL and interventions that reduce this sensory deficit. Together, these observations dictate new strategies of translational research and provide promise for direct therapeutic treatment of the inner ear.
Section snippets
Noise-induced ROS
Until a decade ago, the prevailing view of NIHL was that it was caused by mechanical destruction of the delicate membranes of the hair cells and supporting structures of the organ of Corti (Spoendlin, 1971, Hunter-Duvar and Elliott, 1972, Hunter-Duvar and Elliott, 1973, Hamernik and Henderson, 1974, Hamernik et al., 1974, Hunter-Duvar and Bredberg, 1974, Hawkins et al., 1976, Mulroy et al., 1998), with perhaps some effect of intense noise on blood flow to the inner ear (Perlman and Kimura, 1962
Additional interventions
It is likely that additional factors, intervening at different points in the cell death pathway, may enhance protection against NIHL when delivered in combination with antioxidant agents. Many of these factors could be readily applied to human populations based on demonstrated safety in man; others are further from human application. In the following sections of this review, evidence supporting the utility of other potential interventions is described. Data are drawn from the auditory system
Vasodilation and NIHL
In most tissues, increased metabolism is associated with increased blood flow, which provides additional oxygen to stressed cells. However, in the cochlea, high levels of noise decrease blood flow (Perlman and Kimura, 1962, Lipscomb and Roettger, 1973, Thorne and Nuttall, 1987, Miller et al., 1996, Miller et al., 2006). Decreased blood flow in the cochlea is a direct consequence of noise-induced reductions in blood vessel diameter and red blood cell velocity (Quirk et al., 1992, Quirk and
Steroids
Glucocorticoid receptors are expressed in almost every type of cell, although there is variation in receptor density across cells (Barnes and Adcock, 1993). Glucocorticoid-mediated protection of cells may result from rapid modulation of calcium channels and calcium mobilization. Based on tissue and cell type, glucocorticoids can inhibit (He et al., 2003) or enhance (Zhou et al., 2000, Takahashi et al., 2002) intra-cellular calcium. Yukawa et al. (2005) recently reviewed the divergent effects of
Glutamate excitotoxicity
The application of glutamate (Janssen et al., 1991) or glutamate agonists (Puel et al., 1991, Puel et al., 1994, Le Prell et al., 2004) results in functional deficits and swelling of auditory neurons equivalent to those observed after noise exposure (Robertson, 1983, Puel et al., 1998, Yamasoba et al., 2005). Large concentrations of glutamate are released in response to loud noise, and toxic concentrations of this excitatory amino acid lead to large sodium and potassium ion flux across the
Overview
All of the substances described above modulate calcium channel permeability and/or calcium homeostasis in at least some biological systems. Noise exposure increases calcium concentration not only in afferent dendrites, but also in hair cells (Fridberger and Ulfendahl, 1996, Fridberger et al., 1998). These elevations in intra-cellular calcium have been implicated in hair cell damage and hearing loss post-noise, as deficits induced by noise, chemotherapeutics, or H2O2, can be blocked by calcium
Additivity and/or synergy among factors
Given that none of the interventions tested to date completely prevent NIHL and noise-induced sensory cell death, it would seem reasonable to seek an additive effect with a combination of factors that intervene at multiple sites in the biochemical cell death cascade. Yamasoba et al. (1999) therefore evaluated a combination of an antioxidant (mannitol, a hydroxyl scavenger), a neurotrophic factor (GDNF), and an iron chelator (deferoxamine mesylate, DFO), each of which individually attenuate
Summary
NIHL is a significant clinical issue; reducing the number of individuals afflicted would have broad economic and humanitarian benefit. We now know many of the pathways to cell death initiated by noise, and other environmentally mediated trauma, such as aminoglycoside antibiotics, and chemotherapeutics, as well as the process of aging. Interventions can be directed at preventing initial ROS formation, maintaining cochlear blood flow, restoring calcium balance in cells and in neurons, preventing
Acknowledgements
Support for this research was provided by the National Institutes of Health (NIH-NIDCD R01 DC03820 and P30 DC005188), the General Motors Corporation/United Automotive Workers Union, and the Ruth and Lynn Townsend Professor of Communication Disorders. We thank Dr. Kevin Ohlemiller for helpful suggestions on an earlier version of this manuscript, and Drs. Richard Altschuler, Jochen Schacht, Yoshi Ohinata, and Fumi Shoji, as well as Alice Mitchell and Diane Prieskorn, for their contributions to
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