Pharmacological strategies for preventing cochlear damage induced by noise trauma
Barbara Canlon1, Karin Agerman2, Rene Dauman3, Jean-Luc Puel4
1 Department of Physiology and Pharmacolog, Karolinska Institutet, 171 77 Stockholm, Sweden
2 Department of Physiology and Pharmacolog, Karolinska Institutet, 171 77 Stockholm; Department of Molecular Neurobiology, Karolinska Institutet, Stockholm, Sweden
3 Service d´Oto-Rhino-Laryngologie, Unité d´Audiologie, Hospital Pellegrin, C.H.U. de Bordeaux, Bordeau, France
4 INSERM - U. 254, Laboratoire de Neurobiologie de l'Audition, CHU Hôpital St. Charles, Montpellier, France
Hearing loss induced by noise, as well as in combination with other environmental factors, is a significant health problem throughout the world.
Although most structures in the inner ear can be harmed by excessive sound exposure, the sensory cells are the most vulnerable.
Damage to the stereocilia bundle is often the first structural alteration noted.
Once a large number of hair cells are lost, the nerve fibres to that region also degenerate resulting in an irreversible hearing loss.
At present, the underlying mechanism for cochlear damage induced by noise is not fully understood.
The failure of the adult peripheral auditory system to regenerate after injury is a major clinical problem.
However, a number of experimental applications have recently become available and are effective in reducing the damaging effects of noise.
Current experimental designs include strategies for protecting against injury and are primarily based on the fact that the metabolic state of the cochlea can determine the overall degree of hearing loss induced by noise.
The purpose of the present article is to review the current literature dealing with strategies for protecting against noise trauma.
Keywords: auditory, cochlea, noise trauma, protection
How to cite this article:
Canlon B, Agerman K, Dauman R, Puel J. Pharmacological strategies for preventing cochlear damage induced by noise trauma. Noise Health 1998;1:13-23
How to cite this URL:
Canlon B, Agerman K, Dauman R, Puel J. Pharmacological strategies for preventing cochlear damage induced by noise trauma. Noise Health [serial online] 1998 [cited 2011 Jun 25];1:13-23. Available from: http://www.noiseandhealth.org/text.asp?1998/1/1/13/31781
Reducing the damaging effects of noise: The early studies
During the late 70s and early 80s several intriguing experiments demonstrated that the magnitude of hearing loss induced by noise could be modulated.
It was apparent from these early experiments that manipulations of cochlear metabolism directly altered the subsequent damage induced by noise.
Increasing or decreasing body temperature during noise exposure resulted in an increased or decreased cochlear damage (Drescher, 1976; Henry and Chole, 1984).
In addition, increasing the oxygen supply, or removing the thyroid gland was also shown to protect the ear from noise-induced hearing loss (Berndt and Wagner, 1979).
Furthermore, Joachims et al., (1983) studied the effect of magnesium on noise induced hearing thresholds in normotensive rats and spontaneously hypertensive rats and found that magnesium deficiency resulted in a significant increase in the threshold shift in both strains.
All in all, these early experiments demonstrated that the metabolic state of the cochlea could directly determine the overall sensitivity of this organ and provide protection against subsequent noise trauma.
However, this line of experimentation (i.e protecting against injury) was not continued until advances were made in models of brain injury showing protection against neuronal death.
When these demonstrations were successful in the brain similar applications have been made to the cochlea.
Coupling excitotoxicity to noise trauma
Beside the well described changes in stereocilia and hair cells, postsynaptic damage at the synaptic pole of the inner hair cells is also prominent after acoustic trauma.
It entails a disruption of the dendrite ending of the spiral ganglion neurons below the inner hair cells [Figure - 1], leading to synaptic uncoupling (Beagley, 1965; Spoendlin, 1971; Robertson, 1983 ; Pujol, 1990).
Recently, it has been suggested that dendrite damage might be due to excessive release of neurotransmitter from the inner hair cells, which is toxic (excitotoxic) to the structure and function of spiral ganglion neuron (Pujol, 1990).
Consistent with this hypothesis is the high degree of protection against noise trauma that is observed when the glutamate antagonist kynurenate is applied to the cochlea (Puel et al., 1998). Moreover, a synaptic repair mechanism occurring within the first few days post-exposure is partly responsible for the recovery of temporary threshold shifts after an acoustic trauma (Puel et al., 1998).
While the acute synapse disruption primarily depends on alphaa m i n o - 3 - h y d r o x y - 5 - m e t h y l - 4 - isoxazolepropionic acid (AMPA) and kainate type of receptors (Puel et al., 1994), the repair mechanism involved N-methyl-D-aspartate (NMDA) and metabotropic receptors (Puel et al., 1995; d'Aldin et al., 1997).
This regenerative process does not exclude the possibility that in the case of successive excitotoxic injuries, additive effects could irreversibly damage some neurons, and consequently lower or stop the beneficial effects of re-innervation.
In support of this line of argument, glutamate neurotoxicity has been reported in the developing rat cochlea after systemic administration of glutamate (Janssen et al., 1991).
L-glutamate administered intraperitoneally to developing rats on postnatal days 2 to 9 produced high-frequency threshold elevations.
The major site of peripheral damage was the spiral ganglion neurons in the basal region of the cochlea, where a significant reduction in neurons was noted.
Scanning electron micrographs of surface preparations revealed no significant hair cell death.
Similarly, Juiz et al. (1989) reported that 10 days or more after an intracochlear perfusion of kainate, a subpopulation of spiral ganglion neurons (34%) had degenerated with no apparent damage to cochlear hair cells and supporting cells.
In agreement with the reported selectivity of kainate for glutamaceptive neurons (Coyle, 1983), the neuronal loss induced by kainate was in vitro blocked by the broad spectrum glutamatergic antagonist kynurenate, in a dosedependent manner (Lefebvre et al., 1991). The pathological consequences of sound-induced excitotoxicity is summarised in [Figure - 1].
Coupling NMDA receptors to NO synthesis for noise trauma
The administration of N-methyl-D-aspartate (NMDA) antagonists have been shown to prevent toxic damage to hair cells in guinea pigs treated with aminoglycoside antibiotics (Basil et al., 1996).
It was suggested that the aminoglycosides bind to the polyamine site on the NMDA receptor and by excitotoxic mechanisms results in the destruction of the hair cells.
Regardless of whether hair cells express NMDA receptors, why are the spiral ganglion neurons spared, which certainly express these receptors?
One explanation that has been proposed is that aminoglycoside activation of NMDA receptors on neurons is not lethal by itself, but causes the release of other toxic substances from neurons which in turn damage the cells in the organ of Corti (Ernfors and Canlon, 1996).
Nitric oxide (NO) is a typical retrograde signal in the brain and the concentration at which it is present determines whether it has protective or toxic effects.
Furthermore, NO has been shown to be one of the underlying molecules involved in the cell death following NMDA-mediated excitotic damage in the CNS.
It is possible that NO is a mediator of hair cell damage in the cochlea because: (i) at high concentrations NO causes the death of any type of cell (thus both hair cells and supporting cells would succumb to it), (ii) it is produced by the spiral ganglion neurons (iii) it is known that excess stimulation of NMDA receptors leads to excess NO release, and (iv) by blocking NO synthesis in the cochlea with the inhibitor NG-methyl-L-arginine prevents chemically induced cytotoxicity.
The overproduction of NO would be expected to damage all cell types in the organ of Corti and the NO hypothesis could explain the loss of both hair cells and supporting cells following severe noise damage.
Any toxic effect from the neurons to the hair cells in the organ of Corti are most likely in balance with protective mechanisms also stemming from the spiral ganglion neurons.
Rapid production of oxygen free radicals in hair cells have been implicated in hearing loss induced by noise (Quirk et al., 1994; Yamane et al., 1995; Seidman et al., 1993).
An upregulation of anti-oxidant enzymes in cochlear tissues have been demonstrated after noise exposure (Jacono et al., 1998).
The upregulation of these enzymes would be expected to attenuate threshold shifts induced by noise exposure.
The susceptibility of the cochlea to noise-induced damage is increased by inhibition of glutathione synthesis (Yamasoba et al., 1998).
These increased thresholds were found after a noise exposure that was repeated for several days. However, when a short term noise exposure was investigated, whole tissue levels of glutathione were not altered suggesting that short duration noise exposure does not alter glutathione homeostasis (Lautermann et al., 1997).
It is not enough to just block the NMDA receptors but rather a combined treatment with for example, NMDA receptor blockers, and antioxidant therapy can protect against noise induced hearing loss.
A number of recent studies have shown that the susceptibility of the inner ear to noise trauma can be reduced by prior exposure to an acoustic stimulus.
At present, two distinct paradigms are employed to reduce the susceptibility of the inner ear to noise trauma.
The first uses a lowlevel, non-damaging continuous acoustic stimulus before the traumatic exposure [Figure - 2]. This phenomenon has been termed sound "conditioning" and has been demonstrated on a number of species including guinea pigs, gerbils, rabbits, and rats (Canlon et al., 1988; Ryan et al., 1994; Boettcher et al. 1995; Dagli and Canlon, 1994; 1997, Kujawa and Liberman, 1997; Canlon et al., 1992; Pukkila et al., 1997; White et al., 1998).
The second paradigm uses an interrupted schedule at sound levels that produce a temporary threshold shift during the first few days of exposure.
However, as the daily exposure continues the degree of threshold shift is reduced, in some cases to no threshold shift despite an ongoing exposure.
This reduction has been termed "toughening" or resistance to noiseinduced hearing loss.
Toughening has been demonstrated in chinchillas, guinea pigs, and gerbils (Clark et al., 1987; Sinex et al., 1987; Campo et al., 1991; Franklin et al., 1991; Boettcher, et al., 1992, 1993; Subramaniam et al 1991, Miyakita et al., 1992; Boettcher, 1993; Henselman et al., 1994; Henderson et al., 1994; McFadden et al., 1997; White et al., 1998).
While the underlying mechanism responsible for protection against noise trauma by sound conditioning is not known, neither the middle ear muscles, nor the efferent system seems to play a significant role.
Studies from three different laboratories, using three different species, have shown that the middle ear muscles do not significantly contribute to the protection from acoustic trauma by sound conditioning (Ryan et al., 1994; Henderson et al., 1994, and Dagli and Canlon, 1995).
The role the efferents play in modulating noise damage after sound conditioning is questioned after a report that compared a sham operated sound conditioned group to a deefferented sound conditioned group and showed similar responses to the traumatic stimulus.
It was suggested that stress factors play a significant role in determining the sensitivity of the ear to trauma.
Noise and other types of stress, for example, restraint, have been shown to increase glucocorticoid levels (Rarey et al., 1995; Curtis and Rarey 1995).
An interesting study by Jacono et al. (1998) has shown that a sound conditioning paradigm caused an increase in antioxidant systems.
The finding that low level acoustic stimulation increases endogenous levels of antioxidant systems in the cochlea opens many new avenues for future studies on protecting against noise trauma.
Could the sound-induced increase in endogenous antioxidant systems provide protection against other environmental toxins? Future experiments are needed to address this question.
Reactive oxygen species are implicated in a variety of hearing disorders.
The ultimate fate of free radicals is the induction of membrane lipid peroxidation which leads to alteration in ion homeostasis and energy metabolism and eventual destruction of the plasma membrane.
The subcellular source of oxyradicals is the mitochondria where oxygen radicals are generated during the electron-transport process.
Two oxyradicals that play predominant roles as initiators of membrane lipid peroxidation are the hydroxyl radical and peroxynitrite.
The hydroxyl radical can also interact with nitric oxide to form peroxynitrite. These processes occur in many different acute and chronic degenerative conditions and can lead to a cascade of events that culminate in apoptotic cell death.
The inhibition of free radical generation (antioxidative processes) can protect the membrane from damage and can maintain ion homeostasis and cellular energy metabolism.
Noise and ototoxic drugs affect inner ear function, possibly through free radicals, and are therefore expected to affect cellular defence mechanisms.
Glutathione, an endogenous antioxidant substance, that has been localised primarily to the stria vascularis, has been shown to protect against noise trauma.
The antioxidant system is sensitive towards environmental influences and show differences in cochlear glutathione and glutathione-related enzymes in different species. (Lautermann et al., 1997).
Gentamicin ototoxicity has been shown to depend on dietary factors and to correlate with tissue glutathione levels (Lautermann e al., 1995).
Thus, compounds that could potentially protect against gentamicin ototoxicity may be more correctly assessed in animal models of deficient nutritional states in which endogenous detoxifying mechanisms are compromised.
The inhibition of the generation of reactive oxygen species has been a successful means of protecting against noise-induced hearing loss (Seidman et al., 1993; Quirk et al., 1994; Yamane et al., 1995; Jacono et al., 1998; Yamasoba et al., 1998).
Reduced cochlear blood flow by vasoconstriction has been implicated in noiseinduced hearing loss (Hawkins, 1971).
Ohlsen et al has shown the effectiveness of topical application of vasodilating agents in increasing cochlear blood flow (Ohlsen et al., 1992).
Others have shown that oxygen (i.e. cochlearoxygenation) is a more important factor than CO2 (i.e., as a vasodilator) in protection of the cochlea from noise induced damage (Hatch et al., 1991).
Experiments where all calcium channels were blocked caused a reduction in noise-induced microvascular permeability which in turn can reduce temporary threshold shifts (Goldwyn et al., 1997).
Exposure of noise to the cochlea may result in local vasoconstriction of cochlear vessels, which leads to a decrease in cochlear blood.
This may lead to hypoxia and subsequently formation of free oxygen radicals. Seidman et al have shown that both superoxide dismutase and allopurinol can prevent noise-induced damage, indicating that this damage may be related to free oxygen radicals (Seidman et al., 1993).
Other experiments show that free oxygen radical induced lipid peroxidation is an important mechanism in noise-induced hearing loss (Quirk et al., 1994).
Acoustic trauma and tinnitus
Worthy of note is the frequent occurrence of tinnitus (i.e. auditory perception in absence of sound stimulation) and the overexpression of NMDA receptors after an acoustic trauma (Axelsson and Barrenas, 1991, Puel et al., 1996).
In contrast to AMPA/kainate receptors that simply mediate fast depolarising responses, activation of NMDA receptors can result in longlasting changes in synaptic efficacy, responsible for the induction of long-term potentiation (LTP). Briefly, LTP is a sustained increase in synaptic efficacy following tetanic stimulation of some excitatory pathways, and has attracted wide interest as a potential mechanism for information storage in the brain (i.e. learning and memory).
Although the precise mechanisms underlying this form of plasticity are unknown, NMDA receptor antagonists have been shown to prevent its induction in hippocampal pathways, even though these substances have little effect on excitatory postsynaptic potentials (EPSPs) (see Collingridge et al., 1988).
Subsequent investigations have also demonstrated that NMDA receptor antagonists can suppress epileptiform activity (paroxysmal depolarisations, burst firing) induced in vitro by convulsant drugs, and by kindling-like electrical stimulation, and can block convulsions in many animals models of epilepsy (Dingledine et al., 1990 ; Chapman, 1991).
Thus, one speculation is that, if altered, or excessively stimulated (e.g. resulting from ischaemia/acoustic trauma), NMDA receptors in the cochlea also could give rise to an increased spontaneous and repetitive or "epileptic-like" firing, which could be interpreted as tinnitus by the brain auditory centres.
At first glance, treatment with glutamate antagonists that alter neurotransmission does not seem appropriate to treat hearing loss and tinnitus.
Interestingly, NMDA and metabotropic receptors that appear to be an important component in pathological conditions (i.e, neosynaptogenesis, tinnitus, neuronal death), are those involved to a lesser degree in excitatory synaptic function, making them an attractive therapeutic target.
Another neuropharmacological approach for pathologies linked to glutamate excitotoxicity might also take into account the pharmacology of some lateral efferent agonists.
Numerous neuroactive substances have been found in these synapses: ACh, GABA, dopamine, encephalins, dynorphins, and CGRP (see Eybalin, 1993).
Once again, these molecules, which have limited effects on the normal functioning of the cochlea, are released under pathological conditions such as noise (Drescher et al., 1983 ; Eybalin et al., 1987b, Gil Loyzaga et al., 1993), and could be involved in synaptic plasticity such as the guidance of newly formed dendrites and/or the stabilisation of the IHC synapses (Puel et al., 1995).
What is clear at this point is that there is much work to be done before the above pharmacological speculations can be put into clinical practice.
Future research that relies on molecular information, such as antisense oligonucleotide experiments, knockout strategies, and gene transfer protocols, is still necessary to better understand both physiological and pathological mechanisms underlying synaptic plasticity, control of neuronal excitability, and neuronal death.
Indeed, it is reasonable to assume that subtle molecular mechanisms involved in cochlear function and disease will be more clearly understood in the near future, there are certain restrictions that have to be taken into account for their possible clinical application.
Since the hair cells of the mammalian cochlea do not have the ability to regenerate, we are only left with the hope of finding effective intervention therapies.
A possible concern here is whether, in the therapeutic dose range, these products will cause side effect on the central functions.
Addressing these questions will require the development of a local application of drugs directly into the cochlea.
However, before intervention therapies can be implemented several issues concerning the choice of patients, the route of administration, and the choice of drugs to be applied needs to be determined.
It would be best to reserve in situ cochlear pharmacology for those patients with a normal contralateral ear or with an ear that can easily be fitted with a hearing device.
Decision for the best route of administration will be partially governed by the techniques routinely used in the clinic, and partially by economic soundness.
Two possibilities include an extra-cochlear approach (round or oval window), or, to a direct, intracochlear administration.
The extra-cochlear approach has several disadvantages compared to the intra-cochlear administration. It is most conceivable that the extra-cochlear approach, an invasive operation, will be a one-time procedure.
Taking into the consideration the rapid turnover of perilymph, the therapy drug will be quickly diluted and removed from the perilymph.
As a result of the rapid perilymph turnover, this route of administration may not offer any substantial benefit.
Repeated application would therefore be necessary, but would be unpractical.
It is most likely that cochlear implant patients will have a major role to play in the development of in situ cochlear pharmacology.
The simultaneous implantation of both the cochlear implant electrodes together with a mini-osmotic pump would be possible and the mini-osmotic pump could allow for continuous infusion for weeks.
Even if longer infusion times are required a simple procedure to refill the osmotic pump is all that would be required.
Continued animal experiments are necessary for determining the drug of choice or a combination of drugs as well as their appropriate concentrations. At present, little is known about the long-term effects of drug therapy.
Most animal experiments have ended after either two or four weeks and it is therefore important to gain more information about longer survival times (years) for the morphology and physiology of the hair cells and spiral ganglion neurons.
Our understanding of cochlear protective mechanisms has made significant advances in recent years.
These results have led to new concepts for the homeostasis of the cochlea.
These new concepts consider that the balance of retrograde and anterograde trophic signalling factors determines the overall susceptibility of organ of Corti and spiral ganglion neurons to damage, as schematically shown in [Figure - 3] (Ernfors and Canlon, 1996).
Compromising the organ of Corti will deplete spiral ganglion neurons of neurotrophic support and will eventually result in the death of these cells and disrupting the neurons should deprive hair cells of trophic support causing cell death.
Regardless of the mechanisms of action and whether the effects are direct or not, the fact of the matter is that a giant leap has been made for preventing neuronal and organ of Corti damage and now there are candidate drugs with protective properties for spiral ganglion neurons as well as for cochlear hair cells.
It is conceivable that clinical trials can be performed in the near future and new strategies for preventing hearing loss established.
This study was supported by grants from the Swedish Council for Work Life Research (79-0800), Medical Research Council (09476), Stiftelsen Tysta Skolan, and the Karolinska Institute. A joint publication of PAN partners (European Commission BIOMED 2 concerted action - Contract BMH 4-CT96-0110).
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