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Vink R, Nechifor M, editors. Magnesium in the Central Nervous System [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
Hearing loss is a major public health problem with a large number of causes. Among them, noise-induced hearing loss, drug ototoxicity and sudden sensorineural hearing loss have been proven to result, in part, from metabolic disorders. Metabolic disorders have multiple origins such as ionic, ischemic, excitotoxic and production of cochlear free radicals causing cell death, via necrosis or apoptosis. The efficacy of magnesium, administered either to prevent or to treat hearing damage, has been demonstrated in several studies in animals and in humans, particularly in noise-induced hearing loss. The exact mechanism by which Mg2+ acts is not fully known. Different hypotheses exist including calcium antagonism, vasodilatation, antioxidant and anti-NMDA properties. Because it is a relatively safe and well-known treatment, magnesium therapy, alone or in association, could be of a great interest to improve auditory recovery.
According to the World Health Organization, 278 million people worldwide have moderate to profound hearing loss in both ears. Besides pathologies of unknown origin, such as sudden hearing loss and Meniere’s disease, hearing loss has so many known causes; it would be arduous to list them all. Briefly, it can be due to the aging process, exposure to loud noise, certain medications, infections, head or ear trauma, congenital or hereditary factors, diseases, as well as a number of other causes. In noise-induced hearing loss (NIHL), sudden sensorineural hearing loss (SSHL) or iatrogenic hearing loss (ototoxicity), sensory cell death involves metabolic processes. Pharmacological intervention to prevent or ameliorate the evolution of these hearing impairments, as well as susceptibility factors, have been studied for a number of years in animal models or in humans. Among them, magnesium seems to play an important role. Magnesium therapy is well documented because it is usually prescribed in other pathologies. Its side effects and contraindications are few and it is cheap. Magnesium, which easily crosses the hematocochlear barrier, presents neuro- protective and vasodilatory effects, and is able to limit cochlear damage. These observations have led to many investigations, the aim of them being to evaluate the pertinence of magnesium administration in prevention or treatment in such a hearing impairment. This article presents some arguments that emphasize the interest of magnesium therapy in some forms of hearing loss.
Sound waves are transmitted via the bones of the middle ear to the fluid environment of the inner ear, where the sensory organ is in the cochlea. The human cochlea is a 30-35 mm long coiled tube containing three parallel chambers (Figure 1A): the scala vestibuli and the scala tympani, which both contain perilymph, and the scala media, which contains endolymph. In contrast to perilymph, which is similar to cerebrospinal fluid, endolymph contains a large amount of potassium (154 mM) maintained by the cells of the stria vascularis. The organ of Corti (Figure 1B) is composed of supporting cells and hair cells. Of all the sensory organs, the organ of Corti functions with the smallest number of sensory receptor cells. The human cochlea only contains about 15,000 hair cells, including approximately 3,000 inner hair cells (IHCs) and 12,000 outer hair cells (OHCs). The IHCs form one row (Figure 2A) and are the primary sensory receptors. OHCs are organized into three (and sometimes four) rows along the outer edge of the organ of Corti. The longer stereocilia of the OHCs are connected to the tectorial membrane.
Schematic representation of the inner ear. A: section of the cochlea; B: organ of Corti.
In the hearing process, sound reaches the inner ear and the basilar membrane supporting the hair cells is displaced. When the hair bundle is deflected, transduction channels are opened and K+ enters the hair cells. The depolarisation evoked by this transduction current activates voltage- gated Ca2+channels and Ca2+ influx. In IHCs, increased intracellular Ca2+ causes mobilization of synaptic vesicles and exocytotic release of glutamate at the base of the hair cells. Glutamate release modulates the activity of the auditory nerve fibres by activating specific receptors, among them the glutamate ionotropic receptors (AMPA, NMDA and Kainite) and the metabo- tropic receptors. The OHCs respond quite differently to changes in membrane potential. Their membranes include a protein (prestin), which alters conformation with the membrane potential and forces cell length changes at acoustic frequencies. This mechanism is thought to amplify and tune the mechanical responses of the basilar membrane. This sensory system is so efficient that, near auditory threshold, a sound vibration of less than 0.1 nanometres is detected, corresponding to a stereocilia displacement 10,000 times lower than its diameter (about one micrometre). However, exposure to loud noise can weaken the system.
Excessive noise is the predominant cause of permanent sensorineural hearing loss. Reports from WHO (2004) state that “worldwide, 16% of the disabling hearing loss in adults is attributed to occupational noise, ranging from 7% to 21% in the various subregions”. At least 30 million people in the United States encounter hazardous levels of noise at work, particularly in jobs such as construction, mining, agriculture, manufacturing, transportation and in the military. Moreover, the incidence of NIHL continues to grow, partly due to the growing popularity of portable music players with highly efficient headphones (Zhao et al., 2010). The hearing loss can be caused by a single exposure to very loud sounds (impulse noise) or by repeated exposure to louder sounds over an extended period. It may be temporary (temporary threshold shifts, TTS) or permanent (permanent threshold shifts, PTS). It is frequently associated with tinnitus.
The mechanisms of damage are of dual origin, mechanical and metabolic. Mechanical damage is immediately developed when the movements of the basilar membrane are excessive, thus inducing detachment of the hairs of the tectorial membrane, disconnection of the interciliary bridges (Figure 2D), or even rupture of membranes. Modern research has provided new insights into the biological mechanisms of NIHL such as free radical production (oxidative stress), glutamatergic excitotoxicity, and ionic and ischemic disorders. They are responsible for delayed hair cell death by necrosis and apoptosis.
It has been demonstrated that an increase in reactive oxygen and nitrogen species (ROS and RNS, respectively) is involved in noise trauma (see Henderson et al., 2006 for review). The superoxide radical anion, nitric oxide (NO) and its redox-related forms, in conjunction with an imbalance of antioxidant defences, have been demonstrated to play a significant role in NIHL as they largely participate in cellular mechanisms that underlie hair cell death. ROS ototoxicity is believed to be associated with deleterious cellular effects at multiple sites, including lipid peroxidation, DNA strand breaks, alteration in carbohydrate and protein structures, and a triggering of cell death gene expression, leading to necrosis or apoptosis. Oxidants are also initiators of intracellular cell death signalling pathways that may lead to apoptosis. The noise- induced ROS formation may occur with a delay of 7-10 days following exposure to noise (Yamashita et al., 2004).
Excitotoxicity is a phenomenon of biochemical events, triggered by the interaction of excitatory amino acids with ion channel-bound receptor complexes, that can lead to cell death. During high-level noise exposure, the IHCs are highly active, leading to the release of large amounts of glutamate into the synapses with the auditory fibres. The level of glutamate in the synapses can overstimulate the glutamate receptors, especially the NMDA receptors, and result in high intracellular Ca2+ levels. The increase in cytosolic Ca2+concentration is not only caused by an influx of extracellular Ca2+, but also by the release of calcium ions from intracellular stores such as the endoplasmic reticulum or mitochondria. Dendritic swelling and vacuolization are a result of excessive postsynaptic ion influx into the VIIIth nerve terminals at the inner hair cell synapse (Pujol et al., 1990).
High-level noise stimulation results in a massive entrance of potassium through the apical channels of the stereocilia. Moreover, mechanical damage with ruptures of the membranes lining the endolymphatic spaces, could involve an excessive influx of K+. This increased K+ concentration may be toxic for the hair cells (Zenner, 1986). The consecutive increase in intracellular Ca2+ over-activates a series of enzymes including phospholipases, proteases, and endonucleases. The result is membrane breakdown, depolymerization of microtubules and disruption of protein synthesis.
Unlike most tissues in which increased metabolism increases blood flow to provide additional oxygen to stressed cells, the cochlea shows reduced blood vessel diameter and red blood cell velocity (Quirk and Seidman, 1995) and decreased blood flow (Thorne and Nuttal, 1987) post-noise. This noise-induced vasoconstriction is a direct consequence of noise-induced formation of 8-isoprostane-F2a, a vasoactive by-product of free radicals (Miller et al., 2003). Cochlear ischemia is aggravated in animals with low Mg2+ content (Scheibe et al., 2000a).
These different mechanisms can lead to cell death, which may be more or less rapid, due to necrosis or apoptosis (Yang et al., 2004). Recent studies have revealed that these two types of cell death exist following exposure to intense noise and that apoptosis appears extremely rapidly after the noise stress. Apoptosis has been shown to be the primary cell death pathway in the first day following noise exposure (Hu et al., 2002; 2006).
Contrary to birds or reptiles, a mammal’s auditory hair cells do not regenerate if they are destroyed. Thus, these new metabolic insights bring hope for possible prevention or treatment to limit oxidative stress, ischemia and the apoptosis cascade. A large number of treatments have been tested over the last few years (see Le Prell et al., 2007a; Shibata and Raphael, 2010 for reviews). Among them, magnesium has aroused some interest.
Over a number of years, researchers and clinicians have demonstrated the influence of magnesium in the susceptibility to recover following acoustic trauma. NIHL of guinea pigs was found to increase with decreasing Mg2+ content of the drinking water while the Mg2+ content of the food was low and constant. In Mg- deficient guinea pigs, the hearing threshold shift after 10 days of continuous noise exposure was negatively correlated to the Mg2+ content of the perilymph (Ising et al., 1982). Coherent results were obtained in rats (Joachims et al., 1983). Similarly, electrocochleographic measurements of the auditory threshold shifts induced by impulse noises (Devrière et al., 1991) showed that Mg-deficient animals are slightly more susceptible to this type of noise. This susceptibility is less pronounced than after a long duration exposure to a continuous noise, as observed in the previous experiments (Ising et al., 1982). After exposure to continuous noise, up to 75% of the variance of PTS in guinea pigs could be explained by the level of perilymph Mg2+ (Vormann and Günther, 1993). The increased susceptibility to NIHL with Mg2+ deficit has not only been demonstrated in animal experiments. In a retrospective study in humans, subjective thresholds across frequencies of 3, 4 and 5 kHz were negatively correlated with serum magnesium (Joachims et al., 1987). This finding was the first indication that magnesium status in humans may be one of the factors determining variations in sensitivity to noise-induced hearing loss. Günther et al., (1989) reported that NIHL observed in 24 air force pilots was negatively correlated to serum Mg2+ concentration. However, Walden et al., (2000), exploring the susceptibility of soldiers to NIHL, failed to demonstrate any correlation between audiometric index and body magnesium.
Because Mg2+ deficiency increases the susceptibility to NIHL, several studies have been conducted in animals or in humans to point out the possible prophylactic efficacy of magnesium. Joachims et al., (1983) observed that guinea pigs with physiologically high Mg2+ levels, when exposed to a single shot impulse or a series of impulses, had significantly smaller threshold increases as compared to physiologically low Mg2+ animals. Scheibe et al., (2000b) showed that oral magnesium supplementation significantly reduces TTS and PTS in guinea pigs subjected to a series of impulses. The mean PTS was found to correlate negatively with the total Mg2+ concentration of perilymph and plasma. Conversely, they did not observe any significant effect on PTS following exposure to a gunshot noise. More recently, Attias et al., (2003) explored the activity of the outer hair cells in guinea pigs by means of otoacoustic emission after impulse noise exposure. In animals supplemented with Mg2+, the thresholds were less significantly affected by noise exposure and the audition recovery was faster. In humans, preventive administration of magnesium has also been shown to be effective in noise-related hearing loss. Attias et al., (1994) tested the prophylactic effect of magnesium in human subjects exposed to hazardous noise. The study was carried out in 300 young, normal-hearing recruits who underwent 2 months of basic military training. This training included repeated exposure to high levels of impulse noises while using earplugs. The subjects received an additional drink daily containing either 167 mg magnesium aspartate or a placebo. The NIHL was significantly more frequent and more severe in the placebo group (28.5%) than in the magnesium group (11.2%). Moreover, the severity of the NIHL was negatively correlated to the magnesium content of red and mononuclear cells. This prophylactic effect in humans was confirmed by Attias et al., (2004) for temporary threshold shifts. Subjects were exposed to a traumatizing noise over 10 min in order to produce TTS without PTS. Compared to a placebo, the preventive oral intake of magnesium (122 mg Mg2+ aspartate during 10 days) provided significant protection against TTS. A negative correlation between the blood magnesium levels and the TTS was also noted.
Whilst magnesium is well known as a preventive treatment for sound trauma, it may also be useful therapeutically. In animals submitted to a series of sound impulses, the systemic administration of magnesium significantly reduced hearing loss after 7 days (Scheibe et al., 2001; 2002). This treatment was more effective if it was quickly instigated. Threshold shift reduction 7 days after acoustic trauma in guinea pigs was confirmed using distortion product otoacoustic emissions (DPOAE, a non invasive technique to test OHC function)(Haupt et al., 2003). In another study (Sendowski et al., 2006) it has been shown that a 7-day post-trauma magnesium treatment reduced auditory threshold shift measured seven days after gunshot noise exposure. However, this improvement was temporary, suggesting that it could be potentially beneficial to prolong the magnesium administration. This hypothesis has since been confirmed (Abaamrane et al., 2009). The latter study compared 4 post-NIHL treatments – a 7-day magnesium treatment, a 1- month magnesium treatment, conventional therapy with methylprednisolone, or a placebo. It was demonstrated that 3 months after an impulse noise trauma, the 1-month Mg treatment preserved more hair cells from death (Figure 3), but this preservation was found to be partial. These observations suggest that post- NIHL treatments can be improved if continued beyond the period of one week.
Another track of research concerns combination of different therapies, including magnesium. Treatment with a combination of vitamins A, C, E and magnesium, initiated 1 hour before noise exposure, produced a compelling reduction in NIHL and cell death, while effects of either the antioxidant agents (vitamin A, C, or E) or magnesium alone were small and not statistically reliable (Le Prell et al., 2007b). Thus, the combination of magnesium with other agents could also be of great interest, and suggests that they act at different and complementary levels of the cellular death process.
Various pharmaceuticals are known to impair the auditory system. The best-known substances are the aminoglycoside antibiotics and cisplatin. Both cause high frequency sensorineural hearing loss, which is usually permanent and associated with loss of outer hair cells in the basal turn of the cochlea. Aminoglycoside antibiotics (such as gentamicin, neomycin and kanamycin) are used to treat bacteria not responsive to conventional antibiotics. Their clinical use is limited by toxic side effects that include cochlear toxicity, vestibular toxicity and nephrotoxicity. Amino- glycoside antibiotics possibly cause formation of free radicals by forming complexes with iron, which is vital for normal mitochondrial function. Free radicals can rapidly react with cell constituents, including cell membranes and DNA. The resulting oxidative stress can trigger apoptotic cell death. The intrinsic apoptosis pathway is the major pathway induced by aminoglycosides in the cochlea (Rybak and Withworth, 2005).
Vormann and Günther (1991) demonstrated that Mg deficiency in growing rats aggravated the ototoxic effects of the aminoglycoside antibiotic, gentamicin. Administration of gentamicin to Mg2+ deficient pregnant rats from day 16-20 of gestation produced hearing threshold shifts in the maternal rats as well in their offspring (Vormann and Günther 1991). These data suggest that Mg2+ deficiency is a relevant predisposingrisk factor for the development of ototoxicity induced by some pharmaceuticals. Recently, it has been shown, in the zebrafish model, that extracellular magnesium or calcium ions modulate hair cell death from neomycin and gentamycin, but exert their protective effects through different mechanisms (Coffin et al., 2009). In mammals, preliminary injection of magnesium solution, by means of electrophoresis, reduced the ototoxic effect of kanamicin (Spasov et al., 1999).
Other well-known ototoxic treatments are platinum compounds. Cisplatin is a frequently used chemotherapeutic agent in the treatment of many types of neoplasias, especially of the head and neck (Rybak and Withworth, 2005). The mechanism of antineoplastic action is associated with the selective and persistent inhibition of the deoxyribonucleic acid synthesis (Williams and Whitehouse, 1979). Its side effects include ototoxicity, kidney toxicity, medullar suppression and gastrointestinal disorders. The nephrotoxic effect of cisplatin is severe damage in the renal proximal cells within the thick ascending loop of Henle, manifested by hypomagnesemia. These types of toxicity can impact treatment, as they reduce the chemotherapy dosage, frequency and duration for many patients. Some audiometric studies have reported elevated hearing threshold in 75-100% of patients treated with cisplatin (McKeage, 1995).
The auditory lesions seem to result from free radical-induced damage to many tissues (Kopke et al., 1997; Rybak et al., 1995; Dehne et al., 2001). Oxygen reactive species are generated in the cochlea after exposure to cisplatin (Clerici and Yang, 1996) and such oxidative stress can cause cochlear cell death by apoptosis secondary to the activation of caspase-3 (Garcia-Berrocal et al., 2007; De Freitas et al., 2009). Inner ear cell apoptosis can be triggered by the formation of complexes between cisplatin and the DNA of the damaged cell, preventing the progression of the cell cycle. Cevette et al., (2000) observed a significant increase in otoacoustic emission amplitude (which provides frequency-specific information about OHC function) in two patients undergoing cisplatin treatment supplemented with magnesium. The authors of this study concluded that Mg2+ might be a promising agent against cisplatin ototoxicity. However, the study of Sahin et al., (2006) showed that a Mg2+ rich diet prevented the severe hypomagnesemia that cisplatin causes in guinea pigs, but failed to provide any protection against its ototoxic effect.
The US National Institute for Deafness and Communication Disorders defines SSHL as the idiopathic loss of hearing of at least 30 dB over at least 3 contiguous test frequencies occurring within 3 days. Estimates of the overall incidence of SSHL range from 5 to 20 per 100 000 persons per year (Conlin and Parnes, 2007). Many etiologic causes of SSHL have been proposed, but many remain unconfirmed. In the majority of patients (71%), the aetiology remains idiopathic. A wide range of disorders might lead to the development of SSHL. The theorized major causative factors can be broken down into several categories: 1) viral infection (13%); 2) vascular impairment; 3) immune-mediated mechanisms; 4) inner ear abnormalities; and 5) CNS abnormalities, including tumours, trauma, haemorrhage, infarction and other pathologies (Chau et al., 2010). The lack of understanding of the mechanism of SSHL has rendered the development of a specific treatment difficult, and currently, empirical guidelines are used. Because of the spontaneous recovery rates of 32% to 70% (Colin and Parnes, 2010), some otolaryngologists choose not to treat SSHL. However the most common approach to treatment of SSHL is with systemic steroids in moderate doses. Nageris et al., (2004) evaluated the efficiency of two treatments after SSHL in humans. The first one consisted of corticosteroid and magnesium, and the second one (control) in corticosteroid and placebo. They observed that more patients treated with magnesium experienced hearing improvement, and at a larger magnitude, than control subjects. Gordin and colleagues (2002) reported a significantly greater recovery rate among patients treated with magnesium and carbogen vs patients treated with carbogen alone.
Magnesium plays an essential role in the regulation of most cellular functions. However, it is recognized that magnesium status in humans is often deficient. In the recent French SU.VI.MAX study (the “supplementation en vitamines et mineraux antioxidants” study) of 5,448 subjects, it was shown that 77% of women and 72% of men had dietary magnesium intakes lower than the recommended dietary allowance (Galan et al., 1997). The deficiency is increased by chronic stress, loud noise exposure or chemotherapy with platinum compounds (Galland, 1991; Mocci et al., 2001, Sahin et al., 2006). Scheibe et al., (1999) were the first to study the correlation between the plasma, perilymph and cerebrospinal magnesium contents in the same animal. Contrary to the blood brain barrier, the blood perilymph barrier is not able to concentrate Mg2+ taken up from plasma. Also, the perilymph Mg2+ concentration correlates well with the plasma level, and a Mg2+ deficiency affects perilymph content.
The exact manner by which Mg2+ affects the susceptibility to hearing loss is still unknown, but several mechanisms could be evoked. By its nature, magnesium is a calcium antagonist and therefore blocks the excessive release of calcium, both in the hair cells and in the cochlear vasculature, limiting cell energy depletion and inducing the vasodilatation of arterioles. Through these mechanisms, magnesium could limit ischemia induced by acoustic trauma. Haupt and Scheibe (2002) demonstrated that cochlear blood flow as well as perilymphatic pO2 levels were significantly increased in noise-traumatized animals that received magnesium supplements. Not only does magnesium combat ischemia, but it is also thought to prevent cell damage caused by hypoxia. Konig et al., (2003) noted a protective effect of magnesium on hypoxia-induced hair cell loss in vitro. In other models, high magnesium concentration has been shown to attenuate the hypoxia/ischemia-induced disruption of the mitochondrial membrane potential, a critical event in triggering cell death (Sharikabad et al., 2001). This mechanism is supported by the observation that an increase in the extracellular magnesium concentration led to a decrease in hypoxia induced apoptosis by maintaining the normal ratio of Bax to Bcl-2 proteins involved in determining the survival of cells or their death (Ravishankar, 2001).
Another potential mechanism explaining the Mg2+ efficiency in NIHL or in drug ototoxicity, involves free radical production. Two mechanisms have been suggested (Garcia et al., 1998). It may directly inhibit free radical production, or it may facilitate scavenging of free radicals. Afanas’ev et al., (1995) showed that Mg2+ inhibits reduced NADP oxidase, an enzyme that produces superoxide radical. However, despite the protective effect of magnesium against oxidative stress, as demonstrated in different models (Sharikabad et al., 2001, Bede et al., 2008), no data are currently available about the cochlea.
Lastly, Mg2+ could act on glutamate excitotoxicity, especially in NIHL. Magnesium apparently enhances the survival capability of the cochlear afferents, reducing the effect of glutamate- induced inner hair cell damage (Ehrenberger and Felix, 1995). Magnesium is able to modulate the opening of Na+/Ca++ channels of the NMDA receptors (Mayer et al., 1984). The blockade of the NMDA receptors by Mg2+ is voltage- dependent, but extracellular Mg2+ behaves as a non-competitive NMDA antagonist, without the side effects presented by the other non- competitive NMDA antagonists. In the hearing process, if Mg2+ is low, an excess of Ca2+ could enter hair cells. In turn, more glutamate would then be produced in response to this Ca2+ influx. Increased glutamate would also greatly increase the activity of the NMDA receptor, which is also operating with low magnesium. With the double insult of high glutamate and low Mg2+, a flood of Ca2+ could go through the NMDA channels into the nerve cell, and the energetic system could be compromised.
Hearing loss is a significant clinical issue. We now know many of the molecular pathways leading to apoptotic cell death that are triggered by noise and other environmentally mediated traumas such as aminoglycoside antibiotics and chemo- therapeutics. There is increasing evidence for their similarity, since free radical formation and apoptotic cascades have been implicated in all. Interventions can be directed at preventing initial ROS formation, maintaining cochlear blood flow or blocking apoptosis. A large number of therapeutics, including magnesium, have been tested. Magnesium, by its neuroprotective and vasodilatory effects, has the potency to prevent as well as to limit hearing loss, particularly after noise exposure or sudden sensorineural hearing loss. Magnesium therapy at the recommended dosage appears to be safe with few contraindications (such as severe renal failure). In contrast to other therapeutic agents (like corticosteroids), it easily crosses the perilymph blood barrier and reaches the organ of Corti. The majority of studies have shown that magnesium is partly effective. Using magnesium in combination with other agents could improve recovery after hearing loss.
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