Antioxidant Therapy and Prevention of Free Radical Induced Cell Death

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Free radical formation associated with environmental stress from intense noise, drugs, aging andtrauma play a key role in hearing loss and cell death in the inner ear. Our studies in the auditory

system have demonstrated that antioxidants plus a vasodilator reduce by >75% both noise and

drug (aminoglycoside)-induced inner ear pathology and hearing loss (Le Prell et al., 2007; Le Prell

et al 2012). This formulation is !-carotene (converted in the body to vitamin A), ascorbic acid

(vitamin C), trolox (vitamin E) and the vasodilator magnesium. These agents (ACEMg) are

remarkably effective, synergistically attenuating stress induced hearing loss. The commercial

product is ‘Soundbites’®.’

With increased urbanization and aging population, there has been an enormous increase in age-related sensorimotor disorders and dysfunction. The largest single disorder effecting upwards of

half of the elderly population is the risk of age-related hearing loss (ARHL). This disability affected

by age and the accumulated environmental stresses related to loud noise and ototoxic drugs, has

grown significantly and will continue. Hearing impairment now affects >600M people worldwide

with a cost to world GNP of approximately 2% (WHO). The humanitarian cost of hearing

disabilities in terms of isolation and decreased quality of life and the added economic burden of

health care costs are enormous, and growing. In youth they affect educational opportunities, in

adults job opportunities, productivity and satisfaction, and in aged social and family isolation.

Strategies to effectively reduce the risk of environmental-stress induced hearing loss based on

currently emerging therapies could be of great value in meeting these large unmet medical and

societal needs and reduce associated costs.

The major environmental factors contributing to acquired hearing loss are noise exposure and

ototoxic drugs. In developing countries drug-induced hearing loss is the principal cause of hearing

impairment, including deaf-mutism as a result of ototoxic drug use in children; while in developed

countries the major risk factor for hearing impairment is noise. These factors account for more than

50% of the burden of ARHL. During the past 20 years with a better knowledge of the mechanisms

underlying noise- and drug-induced hearing loss (NIHL, DIHL) an intervention has been defined

that appears to robustly and reliably reduce both NIHL and DIHL. Basic research led to the new

understanding that intense noise and ototoxic drugs induce the formation of free radicals in the

inner ear, which up-regulate genes involved in cell-death pathways resulting in apoptosis; or if the

free radicals are sufficient in number they directly attack cell membranes resulting in necrotic cell

Antioxidant Therapy and Prevention of Free Radical Induced Cell Death

Theory, mechanisms and studies behind Soundbites

by Josef M. Miller, Ph.D.


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death. This new mechanistic understanding enabled the discovery of a formulation of selected

antioxidants which act in different compartments of the cell synergistically to reduce free radical

and their biochemical consequences and a vasodilator which further acts synergistically with theantioxidants to suppress free radicals.

Growing knowledge of the role of free radicals in other diseases and pathology lend credence to

their important role in hearing loss and the promise of Soundbites to treat hearing impairment.

Free radicals play a key role in pathology from a variety of environmental stress factors. While free

radicals are essential for normal cellular biochemistry, in excess free radicals lead to pathology and

are now well recognized as important factors in sensorimotor disorders, as well as other neurologic

diseases associated with the aging process. Free radicals function as triggers to upregulate necrotic

and apoptotic pathways to cell death. They may be either generated as part of the metabolicprocesses (Ames et al, 1993) of the cell or frequently as side effects of environmental stress factors,

as visible light (Agarwal et al., 1993;Oleinick and Evans, 1998) solar and ionizing radiation (Godar

and Lucas, 1995; Godar, 1999; Zhao, et al;, 2007), cigarette smoke (Aoshiba et al 2001; Carnevali et

al., 2003) , hyper- and hypoxia (Budinger et al., 2002; Wang et al., 2003; Wang et al., 2004), drugs

(Forge and Schacht, 2000; Rybak and Ramkumar, 2007), intense noise exposure (Ohinata et al., 2003;

Le Prell et al., 2007). Models detailing the pathways to cell death initiated by free radicals have

been developed, across a broad range of pathologies in the peripheral and central nervous systems;

and importantly the enhanced production of free radicals secondary to cell metabolism and

environmental stress agents with aging has been well documented (for review see: Ryter et al,

2007).

Thus an over guiding driving hypothesis for this work is that free radical formation defines a ‘final

common cell death pathway’ inducing pathology from a vast variety of etiological factors.

Moreover we hypothesize that these factors are potentiated by reduced organ circulation (Miller, et

al, 2003; Le Prell et al, 2007b), a significant feature of the aging process. Evidence on the key role of

free radicals in cell death in these many fields provides a strong theoretical and empirical support

for the likelihood of their importance in hearing impairment. Evidence for efficacy of antioxidant

treatment to prevent free radical-induced pathology in the eye (NIH Age Related Eye Disease

Study, ‘AREDs’) and the ear (Sha and Schacht, 2006) supports our expectation that this antioxidant

intervention will prevent or delay the onset of presbycusis, and prevent loss of residual hearing

following implantation of cochlear devices. Moreover, we argue that the results of our studies will

have broader implication for health care well beyond the area of hearing and hearing impairment.


J.M. Miller, 2011. Revised 2012 | page 2


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ACEMg/Soundbites is currently under NIH supported trials to demonstrate its efficacy to prevent

NIHL in humans. These trials involve teams of scientists from EU countries Spain and Sweden. The

EC Public Health Research Programme grant supports studies in Sweden, Germany and Spain to

demonstrate the efficacy of Soundbites to prevent the loss of residual hearing in patients

undergoing cochlear implant surgery and to enhance performance benefits of cochlear

implantation. These studies will also demonstrate efficacy of Soundbites to prevent age-related

hearing loss in animal models of presbycusis, to define the relationship between level of stress

(noise) and Soundbites dosing, and to provide further knowledge on the basic mechanisms of

stress-related hearing loss and its treatment by Soundbites. The results of these trials hold promise

for the prevention of age-related hearing loss (ARHL) and other stress-related hearing loss, wherefree radical formation is a known component. Thus data indicate that free radicals play a key role in

sensory and neural cell death and loss of residual hearing, with implantation (Abi-Hachem et al,

2010, Dinh and Van De Water, 2009). Hence, Soundbites may both protect residual hearing and

reduce nerve loss with the stress of implantation, which will impact implant benefit outcomes in

young and old patients.

A model of the biochemistry underlying cell death from stress is illustrated on the following page.

The source of cellular energy for normal homeostasis and function are the mitochondria. And in

the process of their normal function they produce both molecular oxygen and partially reducedforms of oxygen. (The electron transport chain of mitochondria ends with cytochrome c and an

oxidase-dependent tetravalent reduction of oxygen to form water. In this process redox carriers

leak additional electrons to oxygen generating free radicals1.) As mentioned a certain number of

free radicals are essential for normal cellular processes: and if there are too many, there are built-in

antioxidant systems that reduce or scavenge the excess, detoxifying the cell.

However, with cellular stress, such as intense noise or direct surgical trauma, there is an increase

demand for energy to maintain a greater level of metabolic activity required of the cell under stress.

In response to that demand mitochondria produce more energy (ATP) and with that generateexcess free radicals. With intense noise exposure we have found a remarkable 40-fold increase in

free radical formation in the tissues of the inner ear (Ohinata el al., 2000). Such vast amounts of free

radicals overwhelm the endogenous antioxidant system and initiate processes that damage the cell.

While mitochondrial activity likely accounts for the major increase in free radical formation with




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noise, additional sources include excitotoxic events in the hyperexcited auditory nerve, and

ischemia/reperfusion, which as mentioned occurs with intense noise exposure in the inner ear.

Excess free radicals may cause cell death by initiating lipid peroxidation of nuclear and cell

membranes, destroying the integrity of the cell and leading to necrotic cell death. This is likely the

path to death in the presence of extreme concentrations of free radicals. In the presence of excess,

but less extreme, free radical cell death is likely by apoptotic mechanisms. Thus free radicals may

up regulate genetic pathways that lead to programmed, apoptotic, cell death via a number ofbiochemical pathways. See figure below. We now know that oxidative stress first initiates an influx

of calcium leading to calcium-dependent-calcineurin/calpain activation, initiating

dephosphorylation of NFAT and activation of the BCL-2 family gene Bad. Bad causes release of

cytochrome c, activation of caspases 9 and 3, and cell death. Second, a caspase-2 dependent




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pathway to cell death can be triggered by free radical-induced DNA damage. Third, caspase-

independent pathways to cell death include release of AIF and EndoG from the mitochondria.

Translocation of EndoG to the cell nucleus results in chromatin condensation and high-molecularmass-chromatin fragmentation and cell death. Fourth, receptor-mediated cell death is initiated with

ligation of death receptors on the surface of the cell, forming a death inducible signaling complex,

which activates pro-caspase-8. Caspase-8 activates caspase-3, leading directly to cell death, and/or

cleaves the gene Bid, resulting in translocation and insertion of the Bax-Bak complex into the

mitochondrial membrane and release of cytochrome c, in turn activating caspases 9 and 3, and cell

death. The caspase-2 dependent pathway differs from the caspase-8 and caspase-9 dependent

pathways in that pro-caspase-2 is activated by DNA damage. Upregulation of a number of these

pathways have been demonstrated in our laboratories in the noise-stressed inner ear, and the

efficacy of interventions that block them have been demonstrated (Minami et al, 2004, Yamashita et

al, 2004, Le Prell et al, 2007, Minami et al, 2007, and Yamashita et al, 2008). This model of the

biochemistry of free radical initiated cell death is entirely consistent with similar models of free

radical initiated pathology in the cardiovascular system, brain and stress induced cell death from

the many etiologies mentioned above. This internal consistency adds to the face validity of the

model for the inner ear and to the generality and potential implications for Soundbites-strategy for

other systems, disorders and diseases.

Given this knowledge, an important feature of the strategy underlying the efficacy of Soundbites is

that it removes the initial cause of cellular stress and pathology. Thus, given the knowledge of the

biochemical pathways to cell death, there are a number of sites along any of these pathways that

could block cell death. We could block the upregulation of one of the caspases or the insertion of

BCL-2 genes into the mitochondrial membrane, or perhaps block release of cytochrome c. However

these are each parallel pathways to cell death and if one is blocked others may take its place. By

blocking the first-cause, free radicals, we eliminate all biochemical paths to cell damage and death.

How ACEMg/Soundbites work

Vitamin C detoxifies by reducing free radicals (for review, see Evans & Halliwell 1999). Scavenging

of oxygen radicals by vitamin C occurs in the aqueous phase (Niki 1987a; Niki 1987b). Vitamin E,

present in lipids in cells (see Burton et al. 1983), is a donor antioxidant that reacts with and reduces

peroxyl radicals and inhibits the propagation of lipid peroxidation (for review, see Schafer et al.

2002). The primary antioxidant action of !-carotene (metabolized to vitamin A in vivo) is to

scavenge singlet oxygen; because singlet oxygen reacts with lipids to form lipid hydroperoxides,




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the removal of singlet oxygen prevents lipid peroxidation (for review, see Schafer et al. 2002). Thus

vitamin C removes free radicals from the water compartments of the cell, while vitamin E removes

them from the lipid compartments, and vitamin c blocks the lipid peroxidation that may beinitiated by free radicals not removed by vitamins C and E.

Why add magnesium?

In most tissues, increased metabolism increases blood flow, which provides additional oxygen.

However, high levels of noise reduce blood vessel diameter and red blood cell velocity and thus

decrease cochlear blood flow (Miller et al. 2002; for review, see Le Prell et al. 2006). Reduced

cochlear blood flow has significant implications for metabolic homeostasis, as cellular metabolism

clearly depends on adequate supply of oxygen and nutrients as well as efficient elimination of

waste products (e.g., Miller et al. 1996). In addition the reduction in blood flow with noise isfollowed by an overshoot with off-set of the noise, causing reperfusion-induced formation of

additional free radical, which synergistically add to those formed during noise.2 Providing agents

that reduce noise-induced vasoconstriction, such as magnesium, betahistine, or hydroxyethyl starch

attenuates NIHL (for review, see Le Prell et al. 2006).

_________________

1There are a number of other mechanisms for the production of free radicals; and while we are only

discussing oxygen free radicals or reactive oxygen species (ROS), there are parallel pathways for the

production of reactive nitrogen species (RNS). Both ROS and RNS, regardless of source, act similarly totrigger cell death pathways to necrosis or apoptosis.

2 In addition to well known effects of magnesium on blood flow, other biochemical mechanisms may further

contribute to the protective effects of magnesium. Magnesium modulates calcium channel permeability,

influx of calcium into cochlear hair cells, and glutamate release (Gunther et al. 1989; Cevette et al. 2003), each

of which may reduce NIHL. Mg is also a NMDA-receptor antagonist. That the NMDA-receptor antagonist

MK-801 reduces the effects of noise, ischemia, or ototoxic drugs (Janssen 1992; Basile et al. 1996; Duan et al.

2000; Konig et al. 2003; Ohinata et al. 2003), suggests another potential protective mechanism for Mg.

Regardless of the specific mechanism of action, Mg supplements clearly attenuate NIHL.

Peer reviewed published papers providing the scientific rationale for this work include:

Yamasoba et al 1998a; Yamasoba et al 1998b; Yamasoba et al, 1999; Shoji et al, 2000a; Ohinata et al,

2000; Shoji et al 2000b; Ohinata et al, 2000; Yamasoba et al; 2001; Altschuler et al; 2002; Ohinata et al,

2003; Zou et al; 2003; Le Prell et al, 2003; Yamashita et al, 2004a; Minami et al, 2004; Yamashita et al.

2004b; Yamashita et al, 2005; Miller et al, 2006; Le Prell et al, 2007a; Le Prell 2007b; Minami et al,

2007; Yamashita et al, 2008




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Antioxidant Therapy and Prevention of Free Radical Induced Cell Death

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