Modern research has provided new insights into the biological mechanisms of noise-induced hearing loss, and with these new insights comes hope for possible prevention or treatment. Underlying the classic set of cochlear pathologies that occur as a result of noise exposure are increased levels of reactive oxygen species (ROS) that play a significant role in noise-induced hair cell death. Both necrotic and apoptotic cell death have been identified in the cochlea. Included in the current review is a brief review of ROS, along with a description of sources of cochlear ROS generation and how ROS can damage cochlear tissue. The pathways of necrotic and apoptotic cell death are also reviewed. Interventions are discussed that target the prevention of noise-induced hair cell death: the use of antioxidants to scavenge and eliminate the damaging ROS, pharmacological interventions to limit the damage resulting from ROS, and new techniques aimed at interrupting the apoptotic biochemical cascade that results in the death of irreplaceable hair cells.

The role of oxidative stress in noise-induced hearing loss.

Functional structure of the organ of Corti: a review.

An integrative model of tinnitus based on a central gain controlling neural sensitivity.

Delayed production of free radicals following noise exposure.

Chemical synaptic transmission in the cochlea.

The anatomic consequences of acoustic overstimulation are explored in this presentation, and attention is directed toward issues where improvements in technology and empirical observation are needed before further advances in our understanding can be achieved. Gains have been made in the last decade in appreciating sound‐induced cochlear injury, but there is now a need to evaluate not only cochlear pathology but also the functional state of the surviving structures. There is a wealth of information about the susceptibility of inner or outer hair cells to acoustic injury; however, the etiology of this injury is not yet fully understood. In addition, current ideas concerning the effects of noise on hair‐cell stereocilia, hair‐cell synapses, the cochlear vascular supply, and the central auditory pathways are in a state of flux and are either undergoing revision or emerging. Other issues, such as the basis of temporary or permanent threshold shift at the cellular level, and the individual differences in susceptibility to injury are in need of a fresh approach. It would seem that the time is now ripe to review our knowledge, recognize its gaps, and develop testable hypotheses concerning the mechanisms of acoustic injury to the ear.

The anatomical consequences of acoustic injury: A review and tutorial.

Neonatal chicks (between 1 and 3 days of age) were exposed to an intense pure tone for 48 hours, then killed immediately after removal from the sound, or 14 days later. Nonexposed age-matched animals served as controls. The inner ear was removed and the auditory receptor organ (the basilar papilla) was prepared for evaluation by scanning electron microscopy. The site of injury on the papilla was described in terms of hair-cell loss and location. The ears with no recovery showed a discrete lesion area, within which there was complete disruption of the hair-cell field and a 35% loss in hair cells. After 14 days' recovery, no hair cell loss could be detected, though the lesion could still be recognized by the disorganization of hair cells in the previously injured area. These data demonstrate hair-cell restoration after severe acoustic injury from intense sound exposure in the neonatal ear.

Hair cell loss and regeneration after exposure to intense sound in neonatal chicks.

Sigma-2 receptors have been implicated in both tumor proliferation and neurodegenerative diseases. Recently the sigma-2 receptor was identified as transmembrane protein 97 (TMEM97). Progesterone receptor membrane component 1 (PGRMC1) was also recently reported to form a complex with TMEM97 and the low density lipoprotein (LDL) receptor, and this trimeric complex is responsible for the rapid internalization of LDL. Sigma-2 receptor ligands with various structures have been shown to induce cell death in cancer cells. In the current study, we examined the role of TMEM97 and PGRMC1 in mediating sigma-2 ligand-induced cell death. Cell viability and caspase-3 assays were performed in control, TMEM97 knockout (KO), PGRMC1 KO, and TMEM97/PGRMC1 double KO cell lines treated with several sigma-2 ligands. The data showed that knockout of TMEM97, PGRMC1, or both did not affect the concentrations of sigma-2 ligands that induced 50% of cell death (EC50), suggesting that cytotoxic effects of these compounds are not mediated by TMEM97 or PGRMC1. Sigma-1 receptor ligands, (+)-pentazocine and NE-100, did not block sigma-2 ligand cytotoxicity, suggesting that sigma-1 receptor was not responsible for sigma-2 ligand cytotoxicity. We also examined whether the alternative, residual binding site (RBS) of 1,3-Di-o-tolylguanidine (DTG) could be responsible for sigma-2 ligand cytotoxicity. Our data showed that the binding affinities (Ki) of sigma-2 ligands on the DTG RBS did not correlate with the cytotoxicity potency (EC50) of these ligands, suggesting that the DTG RBS was not fully responsible for sigma-2 ligand cytotoxicity. In addition, we showed that knocking out TMEM97, PGRMC1, or both reduced the initial internalization rate of a sigma-2 fluorescent ligand, SW120. However, concentrations of internalized SW120 became identical later in the control and knockout cells. These data suggest that the initial internalization process of sigma-2 ligands does not appear to mediate the cell-killing effect of sigma-2 ligands. In summary, we have provided evidence that sigma-2 receptor/TMEM97 and PGRMC1 do not mediate sigma-2 ligand cytotoxicity. Our work will facilitate elucidating mechanisms of sigma-2 ligand cytotoxicity.

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TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death

Within the last 7 years, the protein actin has been identified in the stereocilia and cuticular plate region of the hair cell. An intensive effort has been mounted to describe the structural organization of this protein, to identify actin‐associated proteins in these regions, and to identify the functional role of these proteins. The paracrystalline array of actin and its cross bridges imparts rigidity and stiffness to the stereocilia, which are important in determining their response properties. It also appears that these properties can be changed if the paracrystalline array is damaged by noise exposure. The functional implications of stereocilia rigidity and stiffness, as well as potential contractile mechanisms in the hair cell, are discussed. Finally, it is suggested that changes in the cross‐sectional shape of the stereocilia caused by shearing of actin filaments during stereocilia deflections can be related to the mechano‐electrical events in the plasma membrane of the cell. This may be the link between the transmission of vibrational energy through the sensory accessory structures of the peripheral ear, and the initiation of electrochemical events associated with transduction.

Mark E. Schneider

Papers

The anatomical consequences of acoustic injury: A review and tutorial.

Hair cell loss and regeneration after exposure to intense sound in neonatal chicks.

TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death

The structure and function of actin in hair cells.

Immunocytochemical and quantitative studies of Na+,K+-ATPase distribution in the developing chick cochlea