|Year : 2012 | Volume
| Issue : 4 | Page : 174-178
Noise-induced hearing loss: Recent advances in pharmacological management
Department ENT, Institute of Aerospace Medicine, Bangalore, Karnataka, India
|Date of Web Publication||19-Dec-2012|
Institute of Aerospace Medicine, Vimanpura, Near Hal Airport, Bangalore, Karnataka - 560 017
Source of Support: None, Conflict of Interest: None
Modern day high-performance machines, weapons, aircrafts and locomotives are more powerful, more efficient, and unfortunately, frequently produce high noise levels resulting in Noise-induced Hearing Loss (NIHL). Mechanical hearing protection is essential and effective; however, inherent limitations allow a significant percentage of permanent hearing loss to occur despite protection. Hence, a pharmacological preventative or rescue agent for NIHL forms an important element of a comprehensive approach to maintaining inner ear functional integrity in individuals exposed to noise. The ideal pharmacologic agent would specifically address known mechanisms of acoustic injury, be orally administered, be exceptionally safe, be effective and affordable. Though currently such a pharmacological agent is not available, but the ongoing research is promising. In this article, we discuss various pharmacological agents for prevention and management of NIHL.
Keywords: Noise-induced hearing loss, Management, Pharmacological agents
|How to cite this article:|
Rajguru R. Noise-induced hearing loss: Recent advances in pharmacological management. Indian J Otol 2012;18:174-8
| Introduction|| |
Noise-induced hearing loss (NIHL) is an important etiology of deafness worldwide. Hearing conservation programs are in place and have reduced the prevalence of NIHL, but this disorder is still far too common. Noise is a pervasive and increasing hazard in all developed or developing nations, industrial noise, recreational noise, and military noise exposures being the major sources of noise. Mechanical hearing protection is essential and effective; however, inherent limitations allow a significant percentage of permanent hearing loss to occur despite protection. Hence, a pharmacological preventative or rescue agent for NIHL forms an important element of a comprehensive approach to maintaining inner ear functional integrity in individuals exposed to noise. Though earlier the management of hearing loss largely focused on prevention, or wearing hearing protectors, but during the past two decades research was focused on understanding the biochemical events that can trigger the damage in the Organ of Corti and this knowledge has been used to for development of pharmacological agents that can prevent or reverse the changes caused by noise. In this article pathophysiology of NIHL and pharmacological advances in managing hearing loss are discussed.
| Pathophysiology of Noise-induced Hearing Loss|| |
NIHL can be Acoustic Trauma or Chronic NIHL. , Acoustic trauma refers to a sudden permanent hearing loss caused by a single exposure to an intense sound with sound pressure levels around 13 0-10 40 dB. The degree of hearing impairment seen after acoustic trauma is variable and may range from a mild to profound SNHL. The mechanism of injury in acoustic trauma is direct mechanical injury to the sensory cells of the cochlea.  Chronic NIHL, in contrast to acoustic trauma, is a disease process that occurs gradually over many years of exposure to less intense noise levels, generally high-intensity continuous noise with superimposed or impulse noise.
The development of chronic NIHL progresses through two phases. The first stage is characterized by a temporary threshold shift (TTS), a brief hearing loss that occurs after noise exposure and completely resolves after a period of rest. This is an auditory fatigue and is associated with no or minimal, reversible cell changes. After repeated exposure to noises intense enough to produce TTS, eventually a permanent threshold shift (PTS) will occur. This is the second stage of chronic NIHL and there is an irreversible increase in hearing thresholds. At this point, there has been irreversible hair cell damage. Loud noise injures the sensory hair cells, supporting cells, nervous structures, and blood vessels.  Reductions in the number of capillaries, evidence of vessel occlusion, and alterations of RBC packing density have all been demonstrated in noise damaged ears.
| Cellular Changes in Noise-induced Hearing Loss|| |
At present it is hypothesized that NIHL is expressed with multiple effects on the inner ear. Acoustical overstimulation causes mechanical injury of the organ of Corti. The outer hair cells (OHC) are more vulnerable to noise injury than the inner hair cells (IHC), because of several characteristics including the location of the OHC, which is close to the point of maximal basilar membrane displacement, the direct shearing forces on the stereocilia of the OHC against the tectorial membrane, and the relative lack of supporting cells around the OHC. With prolonged noise exposure, supporting cells and IHC undergo similar changes and eventual loss. After IHC loss, retrograde degeneration of cochlear nerve fibers may also be seen. Early noise-induced injury involves alterations in hair cell membranes which eventually lead to a failure in the regulation of intracellular ionic composition. A chain of events is set off that involves cell swelling or herniation, increased number of lysosomes and changes in essentially all cellular organelles.  The hair cell cilia may become floppy, disordered, splayed, fractured or fused. Some of these changes seen in the cilia are reversible-this may be seen clinically as a TTS. However, at some point the cell is unable to recover from these injuries and degenerates-causing PTS.
There is production of reactive oxygen species (ROS) and other free radical molecules in the cochlea, generation of Nitric Oxide, and co-involvement of Glutamate receptors. , Postulated mechanisms of ROS and other free radicals production in the noise-stressed cochlea include ischemia-reperfusion, metabolically overdriven cochlear mitochondria, and ionic fluxes. Mechanical injury includes microlesions in cell membranes, causing excessive Calcium influx. This results in phospholipase A2 activation, superoxide generation by proteolytically activated xanthine oxidase and formation of nitric oxide (NO) and its breakdown products. 
Glutamate is a major neurotransmitter between the inner hair cell and the afferent cochlear nerve ending.  Excessive sound stimulation leads to excessive synaptic glutamate concentrations causing overstimulation of glutaminergic receptors (glutamate excitotoxicity), invoking metabolic cascades resulting in cell injury and death. There is mitochondrial injury, inhibition of mitochondrial biogenesis, bioenergetic collapse and loss of redox homeostasis, opening of the mitochondrial permeability transition pore and cell death. 
| Pharmacotherapy|| |
The ideal pharmacologic agent would specifically address known mechanisms of acoustic injury, be orally administered, be exceptionally safe, be effective and affordable. Though currently such a pharmacological agent is not available, the ongoing research is promising. Various pharmacological agents and newer developments are discussed in the following sections.
N-Acetyl-L-Cysteine (NAC) is an antioxidant which inhibits lipid peroxidation and scavenges ROS within the cell, indirectly by increasing the intracellular levels of Glutathione (GSH) by acting as a cysteine donor to increase GSH synthesis.  It also reduces the level of caspases and glutamate excitotoxicity.
NAC is effective if administered immediately after noise exposure and in the following days. In animal studies, NAC is found to be a safe and effective molecule, given in a dose of 500 mg/kg intraperitoneal, administered immediately after noise exposure and then during the following two days (cumulative dose of 1500 mg/kg). Also, the molecular weight of NAC is low enough to allow it to be transported across the round window membrane, thus creating a possibility of intra-tympanic administration. However, further research concerning the most beneficial methods of administration, the dose of NAC and an eventual association with other compounds is needed in order to offer adequate protection against all components of noise trauma.
Acetyl-L-Carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps maintain mitochondrial bioenergetics and biogenesis in the face of oxidative stress. It has been used as both a dietary supplement and a drug for the treatment of neurodegenerative diseases and diabetes.  If given before and after the noise exposures, it is shown to decrease the amount of hair cell loss and PTS induced by the continuous noise. Several mechanisms for this action are postulated. ALCAR increases ATP production by supplying acetyl CoA to the tricarboxylic acid cycle as an energy substrate. It can also restore carnitine and cardiolipin levels, enhance the activity of cytochrome c oxidase, enhance mitochondrial DNA transcription, restore the transport of key mitochondrial metabolites, and protect mitochondrial membrane integrity. 
Overall, it appears that ALCAR may enhance the metabolic efficiency of compromised subpopulations of mitochondria, thus decreasing the rate at which mitochondria-derived oxidants are produced.  The doses in adults of 1.5 to 3 g/day for as long as a year demonstrates that ALCAR is very well tolerated.
D-Methionine (MET) a derivative of Disulfiram, exerts its otoprotective action by improving cochlear GSH deficiency state. It provides cysteine for synthesis of GSH. It is also a free radical scavenger. It also inhibits the injury-induced GSH efflux from the injured hair cell. MET can rescue individuals from permanent NIHL when initiated 1 hour after noise exposure. The hair cell-sparing ability of the MET against NIHL was found to be more than 90% in animal studies. 
Glutamate excitotoxicity invokes metabolic cascades resulting in cell injury and death. Glutamate antagonists act through various mechanisms like complete inhibition on interaction with the Glutaminergic receptors (e.g. CGS 19755), direct action at receptor-linked, calcium ion channels (e.g. phencyclidine or MK 801), and interaction with the redox modulatory site of the N-methyl-D-aspartate (NMDA) receptors (DETC-GS).
Carbamethione, a glutamate antagonist, is a metabolite of Disulfiram, a drug used to treat alcoholism since more than fifty years. It acts on NMDA receptors and downregulates NMDA receptor activity, which results in reducing presynaptic release of glutamate and also prevents the consequences of glutamate release postsynaptically.
Prior application of another broad-spectrum glutamate receptor antagonist Kynurenate, can reduce mechanical noise-induced ischemic cochlear injury consisting of destruction of dendrites beneath hair cells. 
Creatine prevents noise-induced change in ATP homeostasis in the cochlea. This reduces the immediate stress-induced pathophysiology. It reduces formation of free radicals and thus prevents cell death. It functions as an energy buffer through creatine kinase, which is abundant in marginal cells of the cochlear stria vascularis. Creatine may also contribute to the maintenance of the endocochlear K + level, thus reducing this immediate effect of noise. Creatine can reduce both temporary (TTS) and permanent (PTS) threshold shifts. 
Tempol is a membrane-permeable radical scavenger that interferes with the formation or the effects of many radicals, thus preventing cell death. Preclinical studies suggest that tempol may be useful in the therapy of cochlear ischemia-reperfusion injury, shock, and inflammation.  Tempol attenuates the PTS only. It has been used to treat human beings topically but not systemically, and side effects of oral consumption in human beings are currently unknown. At present there are no direct data on the dosing that may produce optimal treatment of the inner ear, and present research is focused on dose response studies for systemic administration as well as direct (cannula-osmotic pump) administration of this agent locally into the scala tympani. 
Studies done till now indicate that oral administration creatine and tempol can cross the blood-perilymph barrier, reach the tissues of the cochlea and attenuate NIHL. Also, a combined administration of Creatine and Tempol appears to provide more benefit at16KHz, than Tempol alone. 
Magnesium has been found to have preventive as well as therapeutic effect on noise trauma.  Intracochlear Mg level plays an important role in preventing noise trauma. Magnesium protects against impairment of cochlear microcirculation and oxygenation and systemic microcirculatory impairment.  It also acts as an NMDA antagonist which reduces intracellular glutamate release and contributes to its otoneuroprotective effect. Furthermore, Mg may also contribute to protecting the cochlea against free radicals.
Any kind of Mg therapy in noise trauma should be started as soon as possible after the exposure. In order to improve the therapeutic efficacy, further experimental studies using local application of Mg alone and in combination with another NMDA antagonist or antioxidant and free radical scavenger are in progress. 
Glucocorticoids have been widely used in the treatment of idiopathic sudden sensorineural hearing loss in human beings. When corticoid is administrated one hour after the noise exposure, less threshold shift and less hair cell damage are observed.  The activation of the enzyme Na, K-ATPase by corticoid may contribute to restoration of disturbed cellular osmolarity, electrochemical gradients, and neuronal conduction. , Actually, it seems that corticoids act both at the dendritic and the cellular level. ,
In a basic animal study, the cochlear function 4 hours after transient ischemia was significantly improved by glucocorticoids, prednisolone, and methylprednisolone, at a relatively wide dose range in the case of pre-ischemic administration. On post-ischemic administration, higher doses of glucocorticoids were necessary to ameliorate cochlear ischemia-reperfusion injury. Dehydroepiandrosterone is also an effective agent.  It is considered that glucocorticoids do not promote cochlear blood flow to protect hair cells, but directly protect OHC. ,
| Targeted Steroid Therapy|| |
Transtympanic steroid therapy through a round window microcatheter has shown some hearing improvement in individuals who have not responded to systemic therapy. In this modality, after performing a tympanostomy under general anesthesia, a microcatheter measuring 1.5 to 2.0-mm diameter preloaded with 0.125 ml of methylprednisolone is gently inserted in the bony niche. After surgery methylprednisolone (62.5 mg/ml) is continuously pumped at a rate of 10 microliter per hour continuously for 14 days. Methylprednisolone has anti-inflammatory, antioxidant, antiapoptotic and neuroprotective effects. Apart from avoiding systemic side effects this method achieves higher local concentration of Methylprednisolone. This method is recommended within 6 weeks of the injury in individuals with severe to profound hearing loss. 
| Hyperbaric Oxygen Therapy|| |
HBOT aims to repair microcirculation and there is a demonstrable significant decrease in injured cochlear hair cells following HBOT.  The improved oxygenation of the inner ear activates cell metabolism and the Sodium-Potassium pump, and it leads to a restoration of the ionic balance and the electrophysiologic functions of the cochlea. HBOT is also capable of causing a reduction in hematocrit and blood viscosity, and this can have a rheologic effect in the cochlear region. During HBOT, hypoxic areas of the cochlea can be infused with high partial pressures of oxygen, thus accelerating the biologic cellular mechanisms that are involved in functional recovery.
HBOT is based on the principle that a rise of at least 20% (1.2 bar) in barometric pressure will cause a partial rise in the blood oxygen level. High concentrations of pure oxygen in inspired air produce a considerable increase in the amount of oxygen that is physically dissolved in the blood perhaps as much as 15 times more than what is dissolved at normal atmospheric pressure (1.0 ATA). HBOT not only raises the amount of oxygen that is physically dissolved in the blood, it also increases the level of oxygen that is dissolved in the labyrinthine liquids by diffusion through round window membrane. 10 once-daily sessions (90 minutes per session) of HBOT at 2.2 ATA can be delivered in a multi-person chamber. 
HBOT can be combined with corticosteroids as corticosteroids induce oxygen consumption to mobilize amino acid for glucogenesis and alter glucose utilization by oxygen consuming mechanisms, for significantly improved functional and morphological recovery. 
| Antioxidant Gene Therapy|| |
Antioxidant gene therapy is a potential therapeutic strategy to reduce inner ear oxidative stress. Studies have demonstrated that genes delivered to the inner ear can induce functional enzymes with therapeutic benefits. Overexpression of antioxidant enzymes in the cochlea using adenoviral vectors can effectively protect hair cells and hearing. The inoculation of the adenoviral vectors is done through a cochleostomy at the base of the cochlea of antioxidant enzymes like catalase, Cu/Zn superoxide dismutase, and Mn superoxide dismutase. The superoxide enzymes protect by dismutating superoxide (O 2 - ) into the proradical hydrogen peroxide (H 2 O 2 ), which in turn is inactivated to oxygen and water by catalase or other H 2 O2 -removing enzymes such as glutathione peroxidase. Thus it prevents the formation of Superoxide and highly toxic peroxynitrite. The extent of protection by the antioxidant vectors, though greatest in the basal region of the cochlea, is also extended to the higher turns. 
As systemic administration of antioxidants is possible, so it is not the first treatment of choice, but in case required, it can prove to be an effective mode of therapy.
| Conclusion|| |
To date, of all studies aimed at the prevention of NIHL, none propose that it is entirely preventable, other than by avoiding the exposure, which, in majority of the cases is not possible. Technological advancements in personal hearing protection devices provide protection against NIHL to some extent, but still surveys have shown that NIHL is seen to occur. Hence, there is a need for further research for developing an effective pharmacological agent for management of NIHL, preferably multi-drug therapy, which will be able to address all metabolically induced and mechanically induced stress-related events.
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