Учебники / Auditory Trauma, Protection, and Repair Fay 2008

302 S.H. Green, R.A. Altschuler, and J.M. Miller

earlier findings of Leake and colleagues (Leake et al. 1999). Differences in experimental design and other technical factors might also account for this discrepancy (Miller 2001). An important difference may be the density of surviving SGNs at the time when ES is initiated; that is, higher SGN density is synergistic with ES in promotion of SGN survival, and a “critical mass” of cells is necessary for ES to be successful. Deafening procedures that cause a rapid initial loss of SGNs, e.g., a single dose of aminoglycoside in combination with a loop diuretic, result in a lower density of SGNs at the time when ES is initiated. In contrast, repeated daily administrations of aminoglycoside alone presumably do not cause an immediate loss of all hair cells. The resulting death of SGNs would then be more gradual, even in the initial period, and SGN density higher at the initiation of ES.

Although there is no direct evidence to support the hypothesis that increased cell density in the spiral ganglion synergizes with ES to increase SGN survival, it is consistent with the presence of neurotrophin expression in the spiral ganglion in vivo (Zha et al. 2001) and autocrine and/or paracrine neurotrophic support of SGNs in vitro (Hansen et al. 2001a). Glia may also contribute to paracrine neurotrophic support of SGNs: as noted in the preceding text, spiral ganglion glia produce neurotrophic factors (Hansen et al. 2001a).

7.3 Combining Electrical Stimulation and Peptide Neurotrophic Factors Enhances SGN Survival over Either Alone

Given that neurotrophins and depolarization are additive in promoting survival of cultured SGNs (Hegarty et al. 1997; Hansen et al. 2001b), therapy involving a combination of these factors should be more effective than either alone in enhancing SGN survival after hair cell loss in vivo. Indeed, ES potentiated BDNF-dependent survival of deafferented SGNs in vivo in cats even when ES alone had no effect on SGN survival (Shepherd et al. 2005). Also, combination of ES with GDNF, the latter delivered either by a viral vector (Kanzaki et al. 2002) or by intracochlear perfusion, resulted in enhancement of SGN survival in vivo over GDNF alone. An important remaining question is whether ES alone will maintain SGN survival following withdrawal of neurotrophic factors. If so, this will permit maintenance of SGNs after hair cell loss without a need for continued long-term application of neurotrophic factors.

7.4 Protection of SGNs In Vivo Using Small-Molecule

Therapeutics

To date little in vivo work has been done testing the protective capacity of small molecules in the cochlea. However, on the basis of work in other systems and the initial work in the auditory system, at least three strategies—enhancement of neurotrophic signaling, inhibition of apoptosis, and antioxidants—hold promise, along with many challenges.

et al. 1995). Treatment with GM1 moderately reduces SGN death in vivo after hair cell loss, although severe shrinkage of the surviving SGNs was noted after termination of the GM1 treatment (Leake et al. 2007). However, a promising result of this study is that the trophic effects of GM1 were additive with those of ES and were maintained by continued ES after termination of the GM1.

7.4.2 Inhibition of Apoptosis by Small Molecules

Because apoptosis depends on caspases, caspase inhibition is a potential approach for therapy. The endogenous caspase inhibitors, IAPs, are thought to be particularly promising therapeutic targets and have been investigated in this regard in CNS trauma and neurodegenerative disease (Robertson et al. 2000). Targeting of caspases via IAPs has not yet been used as a protective mechanism for spiral ganglion neurons but inhibition of caspases by this or by the use of cell membrane–permeable inhibitors may be of therapeutic value in SGN protection (Liu et al. 1998). While more associated with excitotoxic cell death, calpains may play a role in the death of SGNs caused by other traumata including loss of neurotrophic support, suggesting that calpain inhibition may have a therapeutic role in SGN protection (Ding et al. 2002).

Inhibitors of JNK or its upstream activators appear promising as therapeutics for neurodegeneration (Bogoyevitch et al. 2004), and JNK inhibitors have been used to protect SGNs (Section 5.4). Since neurotrophic factor deprivation leads to a change in the oxidative state of deafferented neurons, antioxidant treatment may provide another approach to protect SGN from degeneration after hair cell loss.

7.4.3 Antioxidants

Antioxidants (Trolox and acorbic acid) administered either locally (intrascalar) or systemically after ototoxic deafening may reduce degeneration of SGNs and maintain the sensitivity of the auditory nerve to electrical excitation (Miller et al. 2002). Moreover, this efficacy was observed to continue for at least 2 weeks after cessation of systemic administration.

7.5 Regrowth of the Peripheral Process

Studies of humans and experimental animal models have shown that the SGN peripheral process that normally projects to the organ of Corti degenerates quickly after loss of hair cells and is absent even in surviving SGNs (Leake and Hradek 1988; Fayad et al. 1991; Nadol 1997). As a consequence, stimulation by a cochlear implant requires superthreshold depolarization at the SGN cell body or axon within the modiolus, necessitating high stimulating currents that broadly stimulate SGNs. To achieve maximal benefit, therapy to promote SGN survival

304 S.H. Green, R.A. Altschuler, and J.M. Miller

should also promote regrowth of the peripheral process to allow more focal stimulation of SGNs near an electrode. Neurotrophins promote neurite growth from SGNs in vitro (Lefebvre et al. 1994; Hegarty et al. 1997), and some studies suggest that neurotrophic factor therapy can promote in vivo growth of the SGN peripheral process in guinea pigs: neurotrophins or GDNF induce a regrowth of peripheral processes lost within days following hair cell death (Altschuler et al. 1999; Wise et al. 2005), with BDNF-induced regrowth of peripheral processes enhanced by FGF or electrical stimulation (Altschuler et al. 1999).

Depolarization reduces axon growth in cultured SGNs (Hegarty et al. 1997), suggesting that electrical stimulation might have adverse effects on peripheral process growth, maintenance, of physiology in vivo. The particular depolarization-initiated intracellular signals responsible for inhibiting SGN neurite growth are being identified (e.g., Hansen et al. 2003) and may be able to be specifically inhibited as part of therapy. However, patterned electrical activity, as opposed to chronic depolarization, appears to promote rather than inhibit neurite growth in other neurons (Goldberg et al. 2002). This may account for recent observations that have demonstrated positive effects of chronic ES on SGN peripheral processes (Altschuler et al. 1999; Altschuler et al., unpublished observations): ES shortly following hair cell death, and before complete peripheral process degeneration is capable of maintaining these processes; ES initiated weeks after hair cell death, after complete process degeneration, is able to induce a regrowth of processes through the habenula perforata and into the scarred remnants of organ of Corti.

8. Cochlear Blood Flow and Protection

Inner ear blood flow is reduced by intense noise as shown by laser-Doppler measurements (Thorne and Nuttall 1987). This may be a consequence of a noise-induced increase in levels of the vasoconstrictor 8-isoprostane , a lipid proxidation product, in the cochlea (Ohinata et al. 2000a). Direct administration of 8-isoprostane to the anterior inferior cerebellar artery (main blood supply to the inner ear) resulted in a reduction in blood flow. This was blocked by a specific 8-isoprostane antagonist, SQ29548, which also blocked the noiseinduced reduction in CBF (Miller et al. 2003). ROS are presumably involved because glutathione-mono-ethyl ester, a scavenger of oxidative free radicals (Miller et al. 2003) also blocked the noise-induced reduction in CBF. Antioxidants reduce 8-isoprostane formation in the lateral wall and provide protection from noise-induced hearing loss (Ohinata et al. 2003). These data implicate ROS and one of its products, the vasoconstrictor 8-isoprostane , in noise-induced reduction in CBF.

Magnesium, which increases cochlear blood flow, reduces NIHL in guinea pigs (Scheibe et al. 2002) and humans (Attias et al. 2004). This not only indicates that noise-induced reduction in CBF can exacerbate NIHL but also suggests that interventions including vasodilators can be protective against acoustic trauma.

Combination of antioxidants (vitamins A, C, E) with the vasodilator magnesium provides greater attenuation of NIHL than either alone (Le Prell et al. 2007).

9. Protection of Other Cochlear Elements

Damage from noise and ototoxins is not limited to the organ of Corti or spiral ganglion. Other cochlear elements, including the stria vascularis and fibrocytes of the lateral wall, are also affected (Hirose and Liberman 2003; Imamura and Adams 2003; see also Henderson and Hu, Chapter 7; Rybak, Talaska, and Schacht, Chapter 8). These latter effects can contribute directly to hearing loss, for example, by altering the endocochlear potential (Hirose and Liberman 2003), or can have indirect effects on hair cells and SGNs by affecting cochlear homeostasis. Therefore, protection of lateral wall structures might reduce hearing loss caused by noise or other stresses.

10. Summary

The increasing understanding of the basic biology of cell death, protection, and neurotrophic mechanisms has suggested means to reduce the effects of trauma to the inner ear. Generally, traumata that cause permanent hearing loss—e.g., noise, ototoxins, aging—directly affect the hair cells, with spiral ganglion neuron (SGN) death being secondary to the loss of hair cells. However, SGNs are directly susceptible to excitotoxic damage. Known intrinsic protective systems in hair cells include heat shock proteins, antioxidants, and Ca2+ homeostasis; known exogenous systems include the olivocochlear efferents. If these protective systems are overwhelmed by the trauma, hair cells die, typically via known apoptotic pathways but not necessarily in the same fashion in all types of stress. Current strategies for protection of hair cells target enhancing intrinsic protective mechanisms—e.g., treatment with antioxidants—or blocking apoptotic pathways—e.g., inhibition of JNK. In the case of SGNs, protective strategies are based on current understanding of the neurotrophic support SGNs receive from hair cells, the prosurvival intracellular signaling pathways that the neurotrophic stimuli activate and the proapoptotic pathways that they inhibit. Current strategies for protecting SGNs involve enhancing neurotrophic support, e.g., intracochlear application of peptide neurotrophic factors or electrical stimulation by an implanted electrode. In vitro and in vivo studies emphasize the value of combinatorial approaches. One challenge is the identification of the most effective approach(es). A possibly more daunting challenge is the identification of effective means to deliver protective molecules to their intended cellular or subcellular targets, particularly means that will allow translation from animal models to clinical application.

306 S.H. Green, R.A. Altschuler, and J.M. Miller

Acknowledgments. Richard A. Altschuler and Josef M. Miller would like to acknowledge the contributions of Drs. Margaret Lomax, Amy Miller, Annieliese Shrott Fischer, and Mats Ulfendahl and SHG, and the contributions of all the members of the Green lab and the University of Iowa Auditory Neuroscience Group, especially Dr. Marlan Hansen. We thank Drs. Richard Bobbin and, especially, Jochen Schacht for their considerable and helpful contributions to the text. Studies of Drs. Miller and Altschuler were supported by NIH/NIDCD grants R01 DC003820 and P30 DC005188. Studies in the Green lab were supported by NIH/NIDCD grant R01 DC002961 and by the American Hearing Research Foundation.

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