Учебники / Auditory Trauma, Protection, and Repair Fay 2008
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Figure 7.16. Organ of Corti from noise-exposed cochleae. Top is labeled for caspase-8, the bottom for caspase-9.
evidence that calcium homeostasis is central in OHC response to traumatic noise. Vicente-Torres and Schacht (2006) reported increased levels of phosphatase calcineurin and Bcl-xL/Bcl-2-associated death promoter (BAD) following noise exposure. Local application of FK506 and cyclosporin A, calcineurin inhibiting agents, provided significant protection from noise (Minami et al. 2004).
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The course of apoptosis has a short latency. Fifteen minutes after a 1-h noise exposure hair cells were already missing and other cells showed both apoptosis and necrotic-like changes (Hu et al. 2002). Given the 1-h period of the exposure, it is difficult to say when apoptosis begins. To better define the latency of the cell death, the noise exposure was changed to a 1-min series of impulses at 155 dB peak SPL. Cochleae were evaluated at 5 min and 30 min after the exposure. Interestingly, at 5 min after the exposure, there was a small lesion consisting of only apoptotic cells, but at 30 minutes, the size of the lesion expanded and both apoptotic and necrotic cells were found (Fig. 7.17). The necrotic cells may have been cells that begin to die by apoptosis, but convert to necrosis because of a lack of energy to finish the active apoptosis process.
It is clear that the extent of the OHC lesion continues to expand for days after the exposure (Hu et al. 2002; Yang et al. 2004). The direction of expansion is primarily from the center of the lesion toward the basal end of the cochlea and the mechanism driving the expansion is apoptosis, likely to be driven by lipid peroxidation (Yamashita et al. 2004) because lipid peroxidation is self perpetuating (Halliwell and Gutteridge 1999).
12. Cell Death and Impulse Noise
Impulse noise from gunfire, explosions, and so forth generate peak levels of 150 dB SPL or greater. Figure 7.9 illustrates an extreme reaction to such an exposure. There can be much less dramatic examples of mechanical damage. Exposure to impulse noise produces a proliferation of ROS similar to exposure to continuous noise (i.e., concentration at the base of OHCs and neural plexus under IHCs (see Fig. 7.12). Some pathological changes are characteristic of impulse noise, such as disassociation of the OHCs from their supporting Deiters cup (Fig. 7.9). Notice several changes: the OHC has shortened in length and its diameter is larger; the nucleus has migrated from the basal pole to the middle of the cell and, most importantly, the nucleus has shrunk. This may be an example of anoikis, a form of apoptosis where the triggering signal is a loss of attachment to the extracellular matrix. Using the same exposure, the chinchilla’s cochlea expresses p53, a tumor suppressor gene that regulates the cellular response to DNA damage by mediating cell cycle arrest, DNA repair, and cell death (Ko and Prives 1996). The mechanisms involved in p53-mediated cell death remain controversial, and regulation of p53 function is complicated. However, DNA damage and cell stress events including oxidative stress (from ROS) are known to activate p53 (Finkel and Holbrook 2000).
13. Cochlear Responses to Stress from Noise
The cochlea has several lines of defense against stresses from high level noise. At a general body systems level, the auditory system responds to high level noise by triggering both the acoustic middle ear reflex (Henderson 1993; Quaranta
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Figure 7.17. Top view shows propidium iodide labeled organ of Corti 5 min after noise exposure. Note the number of early apoptotic cells. Middle view shows the same area in a cochlea analyzed 30 min after exposure. Note the presence of both apoptotic and necrotic cells. Bottom view shows an organ of Corti colabeled with propidium iodide and caspase-3. Only shrunken nuclei (apoptotic cells) are labeled for caspase-3.
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et al. 1998) and activating the medial olivary system (Rajan and Johnstone 1983; Reiter and Liberman 1995; Rajan 1996; Zheng et al. 1997a). At the level of the organ of Corti, the ear can respond with the expression of cell survival factors, such as heat shock proteins (Yoshida et al. 1999) or bcl-2 (Niu et al. 2003). The ear can also increase the activity of the protective antioxidant system, as demonstrated in a study by Jacono et al. (1998). In the study, chinchillas were exposed to one of three conditions: a conditioning exposure of a 500-Hz octave band of noise for 6 h per day for 10 days, the conditioning exposure plus a 2-day rest period and then a high level noise exposure of 4 h duration, or only the 4-h high level exposure. Interestingly, all three exposures led to increases in the concentration of the antioxidant enzymes catalase, glutathione reductase, and-glutamyl cysteine synthetase in both stria vascularis and the organ of Corti. However, the largest increase in each of the three antioxidant enzymes was in the group that had both the conditioning exposure and the traumatic exposure. It can be argued that the conditioning effects in which the prior prophylactic exposure to moderate noise levels rendered the cochlear antioxidant system more effective. The Jacono et al. (1998) study is a key link in developing pharmacological approaches to protecting the ear from noise. More on protection is found in Green, Altschuler, and Miller, Chapter 10).
14. Summary
Noise causes damage throughout the cochlea but for hearing losses up to about 50 dB the sensory targets are primarily the OHCs, especially in the basal third of the cochlea. Noise causes this damage by creating a large increase in toxic ROS, which in turn initiates cell death by both necrosis and apoptosis. The cell death process continues, primarily by apoptosis, for days after a traumatic noise exposure, albeit at a progressively decreasing rate.
A better understanding of the parameters of cell death (i.e., triggers for the initiation of apoptosis, the driving force behind prolonged cell death after an exposure, factors that influence apoptosis versus necrosis) are interesting issues from a scientific perspective and are already providing direction for the eventual development of drugs for prevention and treatment of acquired hearing loss.
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8
Drug-Induced Hearing Loss
Leonard P. Rybak, Andra E. Talaska, and Jochen Schacht
1. Introduction
1.1 “Ototoxic” Drugs
“Ototoxicity,” drug-induced damage to the auditory or vestibular parts of the inner ear, has probably been in existence since our ancestors began using herbs as remedies for their ailments (Schacht and Hawkins 2006). After all, some of the most powerful ototoxic drugs known today are derived from natural sources: the aminoglycosides, synthesized by soil-dwelling bacteria. Other prominent ototoxic drugs, although causing only temporary threshold shifts, are quinine and salicylate, both derived from tree bark. While the recognition of the cochlear and vestibular detriments exerted by drugs goes back centuries, the problem of ototoxicity was catapulted into the medical and public awareness in 1944 with the arrival of streptomycin, the first aminoglycoside antibiotic (Schatz et al. 1944). Hailed as the long-sought cure for tuberculosis and other gram-negative infections, streptomycin also very quickly revealed its destructive power to the vestibular system (Hinshaw and Feldman 1945).
Since then, with the growing appreciation of potential side effects to the inner ear, other drugs were found that affected hearing or balance. Antimicrobial agents such as chloramphenicol, erythromycin, polymyxin B, and vancomycin have been sporadically associated with ototoxic side effects, as have topical disinfectants such as chlorhexidine. Cisplatin brought the success of cancer chemotherapy at the price of hearing loss in many patients. Loop diuretics (ethacrynic acid, bumetanide, and furosemide) gained unfavorable prominence in part for their own reversible effects on the auditory system but mostly as potentiating agents when given together with aminoglycoside antibiotics. The combination of these two classes of drugs has devastating effects on the auditory system even if the concentration of either drug alone would prove innocuous. Also of concern as potentially ototoxic agents are organometals such as organotins and organic mercury preparations as well as the industrial solvents toluene and styrene. While the organometals can have profound toxicity by themselves, the solvents tend to interact adversely with noise exposure, jeopardizing those who work in industrial environments.
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Because of the sheer number of patients affected and because of the irreversible nature of their effects on the inner ear, aminoglycoside antibiotics and cisplatin command the most attention today among potentially ototoxic medications. This chapter therefore focuses on these classes of drugs.
2. History
2.1 Cisplatin
Cisplatin was first synthesized by Peyrone in 1845, and hence is also known as Peyrone’s chloride (Rosenberg 1980). Its chemical structure was determined in 1893 by Werner as an inorganic complex consisting of a central atom of platinum surrounded by chloride and amine groups in the cis position (Fig. 8.1a). Its biological effects, however, appear to have gone unnoticed for a century. In 1965, Rosenberg et al. discovered some unusual effects in experiments with Escherichia coli subjected to a current that was delivered between platinum electrodes. Individual cells that normally are rods of about 1 by 5 μm were elongated into filaments up to 300 times their original length under the influence of this current, due to a stable form of platinum released from the electrodes. The principal compound involved was Peyrone’s chloride, or cis-dichlorodiammine platinum (II).
The introduction of cisplatin as an antineoplastic agent was primarily based on studies beginning in the 1960s showing its effectiveness in retarding the growth of sarcoma 180 in mice and increasing the survival of mice bearing the highly metastatic L1210 leukemia (Rosenberg et al. 1969). Among several platinum compounds, cisplatin had the greatest efficacy against a wide variety of animal tumors. The drug exhibited: (1) marked antitumor activity; (2) broad-spectrum activity against drug-resistant as well as drug sensitive tumors; (3) efficacy against slowly growing as well as rapidly growing tumors; (4) activity against a tumor insensitive to “S” phase inhibitors; (5) induction of regression of transplantable tumors induced by viruses as well as chemicals; (6) activity in a variety of species; (7) effectiveness against disseminated as well as solid tumors; and (8) potency in rescuing animals with advanced tumors who were near death (Rosenberg 1973). Subsequent studies revealed efficacy against
H3N NH3
Pt
Cl Cl
Cisplatin |
Gentamicin |
Figure 8.1. Structures of cisplatin and gentamicin.