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Excitotoxins - the ultimate brainslayer

by South MA

Glutamic acid (also called " glutamate " ) is the chief excitatory

neurotransmitter in the human and mammalian brain (1-3). Glutamate neurons make

up an extensive network throughout the cortex, hippocampus, striatum, thalamus,

hypothalamus, cerebellum, and visual/auditory system (4). As a consequence,

glutamate neurotransmission is essential for cognition, memory, movement, and

sensation (especially taste, sight, hearing) (3). Glutamate and its biochemical

" cousin, " aspartic acid or aspartate, are the two most plentiful amino acids in

the brain (5). Aspartate is also a major excitatory neurotransmitter and

aspartate can activate neurons in place of glutamate (1,2).

Glutamate and aspartate can be synthesized by cells from each other,

and glutamate can be made from various other amino acids, as well. (5) Glutamate

and aspartate are both common in foods also. Wheat gluten is 43% glutamate, the

milk protein casein is 23% glutamate, and gelatin protein is 12% glutamate. (5)

One of the commonest food additives in the developed world is MSG

(monosodium glutamate), a flavor enhancer. By 1972 576 million pounds of MSG

were added to foods yearly, and MSG use has doubled every decade since 1948 (2).

Aspartic acid is one half of the now ubiquitous sweetener aspartame

(NutraSweet®), which is the basis of diet desserts, low-calorie drinks, chewing

gum, etc. (2,6) Thus, even a superficial look at glutamate/aspartate in brain

chemistry, foods, and food additive technology indicates a major role for them

in our lives. Without normal glutamate/aspartate neurotransmission, we would be

deaf and blind mental and behavioral vegetables. Yet ironically glutamate and

aspartate are the two major excitotoxins out of 70 so far discovered (1-3,6).

Excitotoxins are biochemical substances (usually amino acids, amino acid

analogs, or amino acid derivatives) that can react with specialized neuronal

receptors - glutamate receptors - in the brain or spinal cord in such a way as

to cause injury or death to a wide variety of neurons (1-3,8-10).

A broad range of chronic neurodegenerative diseases, such as

Alzheimer's disease, Parkinson's disease, Huntington's chorea, stroke

(multi-infarct) dementia, amyotrophic lateral sclerosis and AIDS dementia are

now believed to be caused, at least in part, by the excitotoxic action of

glutamate/aspartate (1-3,7-10). Even the typical memory loss, confusion, and

mild intellectual deterioration that frequently occurs in late middle age/old

age may be caused by glutamate/aspartate excitotoxity (2,6). Acute diseases

and medical conditions such as stroke brain damage, ischemic (reduced blood

flow) brain damage, alcohol withdrawal syndrome, headaches, prolonged epileptic

seizures, hypoglycemic brain damage, head trauma brain damage, and hypoxic (low

oxygen) /anoxic (no oxygen) brain damage (e.g. from carbon monoxide or cyanide

poisoning, near-drowning, etc.) are also believed to be caused, at least in

part, by glutamate/aspartate excitotoxicity (1-3, 7-11). Medical research is

focusing more and more on ways to combat excitotoxicity. A drug called

" memantine " which blocks the main glutamate-excitotoxicity site in neurons - the

NMDA glutamate receptor (more on this later) - has been used clinically in

Germany with significant success in treating Alzheimer's disease since 1991.

(12) Memantine's NMDA glutamate-receptor blocking action has also shown

promise in Parkinson's disease, diabetic neuropathic pain, glaucoma, HIV

dementia, alcohol dementia, and vascular (stroke or arteriosclerosis - caused

dementia (12). (12).

Experimental NMDA - glutamate receptor blockers such as MK-801

(dizocilpine) have also demonstrated the ability to reduce or eliminate brain

damage from acute conditions such as stroke, ischemia/hypoxia/anoxia, severe

hypoglycemia, spinal cord injury and head trauma (1-3). Yet the few available

clinical or experimental excitotoxicity-blocking drugs so far discovered have

significant side effect potential - they may block normal, essential glutamate

neurotransmission as well as excitotoxicity (1-3,12). Fortunately, a review of

the basics of glutamate excitotoxicity reveals a host of preventative

nutritional/life extension drug strategies that will minimize or even eliminate

the excitotoxic " dark side " of glutamate/aspartate.

EXCITOTOXICITY 101

Glutamate and aspartate are neurotransmitters. Neurotransmitters

are the chemicals that allow neurons to communicate with and influence each

other. Neurotransmitters serve either to excite neurons into action, or to

inhibit them. Neurotransmitters are stored inside neurons in packages called

" vesicles. " When an electric current " fires " across the surface of a neuron, it

causes some of the vesicles to migrate to the synapses and release their

neurotransmitter contents into the synaptic gap. The neurotransmitters then

diffuse across the gap and " plug in " to receptors on the receiving neuron. When

enough receptors are simultaneously activated by neurotransmitters, the neuron

will either " fire " an electric current all over its surface membrane, if the,

transmitter/receptors are excitatory, or else the neuron will be inhibited from

electrically discharging, if the neurotransmitter/receptors are inhibitory. All

the neural circuitry of our brains work through this interacting " 'relay race "

of neurotransmitters inducing electrical activation or inhibition.

Glutamate receptors are excitatory - they literally excite the

neurons containing them into electrical and cellular activity. There are 4 main

classes of glutamate receptors: the NMDA (N-methyl-D-aspartate) receptor, the

quisqualate/AMPA receptor, the kainite receptor, and the AMPA metabotropic

receptor. Each of these receptors has a different structure, and has somewhat

different effects on the neurons they excite. The NMDA is the most common

glutamate receptor in the brain (13). The NMDA, kainite and quisqualate

receptors all serve to open ion channels. Looking at the NMDA receptor diagram,

the NMDA receptor is the most complex, and had more diverse and potentially

devastating effects on receiving neurons than the others. When glutamate or

aspartate attaches to the NMDA receptor, it triggers a flow of sodium (Na) and

calcium (Ca) ions into the neuron, and an outflow of potassium (K). It is this

ion exchange that triggers the neuron to " fire " an electric current across its

membrane surface, in turn triggering a neurotransmitter release to whatever

other neurons the just-fired neuron synaptically contacts. The kainite and AMPA

ion channels primarily permit the exchange of Na and K ions, and generally cause

briefer and weaker electric currents than NMDA receptors. Thus, when

glutamate/aspartate acts through kainite/AMPA receptors, it is weakly

excitatory, but when glutamate/aspartate act through NMDA receptors, they are

strongly excitatory. (14) NMDA receptor activation is the basis of long-term

potentiation, which in turn is the basis for memory consolidation and long-term

memory formation. (14)

Looking at the NMDA receptor diagram it shows that there are

receptor sites for chemicals other than glutamate. The zinc site can be

occupied by the zinc ion, and this will block the opening of the ion channel.

The PCP site can be occupied by the drug PCP ( " angel dust " ), an animal

tranquilizer; ketamine, an anesthetic; MK-801, an experimental NMDA antagonist;

or the previously mentioned meantime. When the PCP is occupied, the opening of

the ion channel is blocked, even when glutamate occupies its receptor site.

(1-3) The mineral magnesium (Mg) can occupy a site near to, or perhaps

identical with, the PCP site. Magnesium blocks the NMDA channel in a " voltage

dependent manner. " This means that as long as the neuron is able to maintain its

normal resting electrical potential of -90 millivolts, the magnesium blocks the

ion channel even with glutamate in its receptor.

However, if for any reason (e.g. not enough ATP energy to maintain

the resting potential) the surface membrane electrical charge of the cell drops

to -65 millivolts, allowing the neuron to fire, the magnesium block is overcome,

and the channel opens, allowing the sodium and calcium to flood the neuron.

(1-3) After the neuron has fired, membrane pumps then pump the excess sodium

and calcium back outside the neuron. (15) This is necessary to return the neuron

to its resting, non-firing state. Neurons in a resting state prefer to keep

calcium inside the cell at a level only 1/10,000 of that outside, with sodium

levels 1/10 as high as outside the neuron (15) These pumps require ATP energy

to function, and if neuronal energy production is low for any reason

(hypoglycemia, low oxygen, damaged mitochondrial enzymes, serious B vitamin or

CoQ10 deficiency, etc.), the pumps may, gradually fail, allowing excessive

calcium/sodium build up inside the cell. This can be disastrous. (1-3)

CALCIUM, THE EXCITOTOXIC " HIT MAN "

Normal levels of calcium inside the neuron allow normal functioning,

but when excessive calcium builds up inside neurons, this activates a series of

enzymes, including phopholipases, proteases, nitric oxide synthases and

endonucleases.(1,3) Excessive intraneuronal calcium can also make it impossible

for the neuron to return to its resting state, and instead cause the neuron to

" fire " uncontrollably. (1,3) Phospholipase A2 breaks down a portion of the cell

membrane and releases arachidonic acid, a fatty acid. Other enzymes then

convert arachidonic acid into inflammatory prostaglandins, thromboxanes and

leukotrienes, which then damage the cell. (1,3) Phospholipase A2 also promotes

the generation of platelet activating factor, which also increases cell calcium

influx by stimulating release of more glutamate. (3) And whenever arachidonic

acid is converted to prostaglandins, thromboxanes, and leukotrienes, free

radicals, including superoxide, peroxide and hydroxyl, are automatically

generated as part of the reaction (1-3, 16). Excessive calcium also activates

various proteases (protein-digesting enzymes) which can digest various cell

proteins, including tubulin, microtubule-proteins, spectrin, and others. (1,3)

calcium can also activate nuclear enzymes (endonucleases) that result in

chromatin condensation, DNA fragmentation and nuclear breakdown, i.e. apoptosis,

or " cell suicide " . (3) Excessive calcium also activates nitric oxide synthase

which produces nitric oxide. When this nitric oxide reacts with the superoxide

radical produced during inflammatory prostaglandin/leukotriene formation, the

supertoxic peroxynitrite radical is formed (3,17). Peroxynitrite oxidizes

membrane fats, inhibits mitochondrial ATP-producing enzymes, and triggers

apoptosis (17). And these are just some of the ways glutamate -NMDA stimulated

intracellular calcium excess can damage or kill neurons!

GLUTAMATE METABOLISM

Excitatory neurons using glutamate as their neurotransmitter

normally contain a high level of glutamate (10 millimoles per liter) bound in

storage vesicles. (3) The ambient or background level of glutamate outside the

cell is normally only about 0.6 micromoles per liter, i.e. about 1/17,000 as

much as inside the neuron. (3) Excitotoxic damage may occur to cortex or

hippocampus neurons at levels around 2-5 micromoles/liter. (3) Therefore the

brain works hard to keep extracellular (synaptic) levels of glutamate low.

glutamate pumps are used to rapidly return glutamate secreted into synapses back

into the secreting neuron, to be restored in vesicles, or to pump the glutamate

into astrocytes (glial cells), non-neural cells that surround, position, protect

and nutrify neurons. (2,3) These (2,3) These glutamate pumps also require ATP

to function, so that any significant lack of neuronal ATP, for any reason, can

cause the glutamate pumps to fail. This then allows extracellular glutamate

levels to rise dangerously. (2,3) If a glutamate neuron dies and dumps its

glutamate stores into the extracellular fluid, this can also present a serious

glutamate-excess hazard to nearby neurons, especially if glutamate pumps are

unable to quickly remove the spilled glutamate. (3) When glutamate is pumped

into astrocytes, which is a major mechanism for terminating its excitatory

action, the glutamate is converted into glutamine. Glutamine is then released

by the astrocytes, picked up by glutamate-neurons, stored in vesicles, and

converted back to glutamate as needed. (3) This glutamate-glutamine conversion

also requires ATP energy, however, and this anti-excitotoxic mechanism is also

at risk if cellular energy production is comprises for any reason. (3) Also,

excessive free radicals can prevent glutamate uptake by astrocytes, thereby

significantly (and dangerously) raising extra cellular glutamate levels (18).

(18).

EXCITOTOXICITY: THE BACKGROUND FACTORS

From this brief discussion of the mechanisms of NMDA-glutamate

excitotoxicity, it should be clear that there are 5 main conditions which allow

glutamate to shift from neurotransmitter to excitotoxin:

1) inadequate neuronal ATP levels (whatever the cause);

2) inadequate neuronal levels of magnesium, the natural, non-drug

calcium channel blocker;

3) high inflammatory prostaglandin / leukotriene levels (caused by

excessive glutamate-NMDA stimulated calcium invasion);

4) excessive free radical formation (caused by prostaglandin /

leukotriene formation and/or insufficient intracellular antioxidants/free

radical scavengers;

5) inadequate removal of glutamate from the extracellular (synaptic)

space back into neurons or into astrocytes.

Addressing each of these conditions will provide appropriate

nutritional/life extension drug strategies to minimize excitotoxicity.

MSG AND ASPARTAME

MSG and aspartame are 2 of the most widely used food additives in

the modern world. MSG is a flavor enhancer (2), and aspartame is an artificial

sweetener which is the methyl ester (compound) of the amino acids phenylalanine

and aspartic acid (6). MSG is now used in a wide variety of processed foods:

soups, chips, fast foods, frozen foods, canned foods, ready-made dinners, salad

dressings, croutons, sauces, gravies, meat dishes, and many restaurant foods

(2,7). And MSG is added not only in the form of pure MSG. but is also added in

more disguised forms, such as " hydrolyzed vegetable protein. " " natural flavor, "

" spices, " " yeast extract. " " casemate digest. " etc. These additives may contain

20-60% MSG (2,7). Hydrolyzed vegetable protein is made by boiling down scrap

vegetables in a vat of acid, then neutralizing the mixture with caustic soda.

The resulting brown powder contains 3 excitotoxins: glutamate, aspartic acid,

and cysteic acid. (2)

Aspartame is now the most widely used artificial sweetener, and is

the basis for a whole industry of diet desserts, low-calorie soft drinks,

sugar-free chewing gum, flavored waters, etc. (2,6) Upon absorption into the

body, aspartame breaks down into phenylalanine, aspartate, and methanol (wood

alcohol), a potent neurotoxin. (2,6) Between 1985 and 1988 the U.S. Food and

Drug Administration received about 6,000 consumer complaints concerning adverse

reactions to food ingredients. 80% of these complaints concerned aspartame!

EXCITOTOXIN RESEARCH: THE EARLY YEARS

In 1957, a decade after the widespread introduction of MSG into the

American food supply, two ophthalmology residents, Lucas and Newhouse,

discovered that feeding MSG to newborn mice caused widespread damage to the

inner nerve layer of the retina. Similar, though less severe destruction was

also seen upon feeding MSG to adult mice. (7) In 1969, Dr. Olney, a

neuroscientist and neuropathologist, repeated Lucas and Newhouse's experiments.

His research team discovered that MSG also caused lesions of the various nuclei

of the hypothalamus, a key brain region that controls secretion of hormones by

the pituitary gland. They also found that the MSG-fed newborn mice became

obese, were short in stature, and suffered multiple hormone deficiencies. (7)

By 1990 it was known that glutamate is the principal neurotransmitter of

hypothalamic neurons (19), making this key neuroendocrine region especially

sensitive to glutamate excitotoxicity. Olney has continued to be a pioneer in

excitotoxin research, and he coined the term " excitotoxin " in the late 1970s to

describe the neural damage that glutamate, aspartate, and other similar

chemicals can cause. (8)

MSG AND ASPARTAME: THE HARSH TRUTH

Defenders of the widespread use of MSG and aspartame in the world's

food supply rest their belief in the safety of MSG and aspartame on one main

premise: the protective power of the blood-brain barrier. (2,7) It is claimed

that even if dietary MSG/aspartame significantly raise blood levels of glutamate

and aspartate, the brain will not receive any extra glutamate/aspartate due to

the protective blood-brain barrier. (2,7) However, there are many reasons why

this claim is false. The animal experiments cited to back this assertion are

usually acute studies - that is, a single test dose of MSG or aspartame is

given, and no significant elevation of brain glutamate or aspartate is found.

(2) Yet humans eating MSG/aspartame-laced foods and drinks don't just get a

single daily dose. Those who consume large quantities of packaged, processed,

or restaurant foods frequently imbibe MSG/aspartame from breakfast to bedtime

snack, even drinking aspartame-sweetened flavored waters between meals. Toth

and Lajtha found that when they gave mice and rats aspartic acid or glutamate,

either as single amino acids or as liquid diets, over a long period of time

(days), brain levels of these supposedly blood-brain barrier-excluded

excitotoxins rose significantly - aspartic acid by 61%, glutamate by 35%. (20)

To further worsen matters, humans concentrate MSG in their blood

5 times higher than mice from a comparable dose, and maintain the higher blood

level longer than mice. (2) In fact, humans concentrate MSG in their blood to a

greater degree than any other known animal, including monkeys. (2) And children

are 4 times more sensitive to a given MSG dose than adults. (2) Although food

manufacturers in the U.S. removed pure MSG from their infant and children's

foods in 1969 based on Olney's pioneering research (and Congressional pressure),

they continued to add hydrolysed vegetable protein to baby foods until 1976, and

continue to this day to add MSG-rich caseinate digest, beef or chicken broth

containing MSG, and " natural flavoring " (a disguised MSG source) to

baby's/children's foods. (2) Since excess glutamate can affect infants' and

children's brain development, possibly causing " miswiring " that may lead to

attention deficit disorder, autism, cerebral palsy, or schizophrenia, babies and

young children are especially vulnerable to glutamate/aspartate toxicity. (2,9)

It has also been discovered that there are glutamate receptors on

the blood-brain barrier. (7) Glutamate appears to be an important regulator of

brain capillary transport and stability, and over-stimulation of blood-brain

barrier NMDA receptors through dietary MSG/aspartame - induced high blood levels

of glutamate/aspartate may lead to a lessening of blood-brain barrier exclusion

of glutamate and aspartate. (7) There are also a number of conditions that may

impair the integrity of the blood-brain barrier, allowing MSG/aspartate to seep

through. These include severe hypertension, diabetes, stroke, head trauma,

multiple sclerosis, brain infection, brain tumor. AIDS, Alzheimer's disease and

ageing (2,7). Certain areas of the brain, called the " circumventricular

organs. " are not shielded by the blood-brain barrier in any case. These include

the hypothalamus. the subfornical organ, the organium vasculosum. the pineal

gland, the area postrema, the subcommisural organ, and the posterior pituitary

gland (2). The research of Dr. M. Inouye. using radioactively labeled MSG,

indicates that MSG may gradually seep into other brain areas following initial

brain entry through the circumventricular organs (2).

Yet another issue that makes the blood-brain barrier defense of

MSG/aspartame irrelevant is brain glucose transport. Glucose is the primary

fuel the brain uses to generate its ATP energy. Continual adequate brain ATP

levels are needed, as noted earlier, to prevent glutamate/aspartate from

shifting from neurotranmitters to excitotoxins. Creasey and Malawista found

that feeding high doses of glucose to mice could decrease the amount of

glutamate entering the brain by 35%, with even higher glutamate doses leading to

a 64% reduction in brain glucose content (21). Since the brain is unable to

store glucose, this glutamate effect alone could be a major basis for promoting

excitotoxicity.

MSG/aspartame defenders also like to point out that glutamate and

aspartate are natural constituents of food protein, which is generally

considered safe, so why the concern over MSG/aspartame (2)? Yet there is a key

difference between food-derived glutamate/aspartate and MSG/aspartame. Food

glutamate/aspartate comes in the form of proteins, which contain 20 other amino

acids, and take time to digest, slowing the release of protein bound

glutamate/aspartate like a " timed-release capsule. " This in turn moderates the

rise in blood levels of glutamate/aspartate. Also, when glutamate and aspartate

are received by the liver (first stop after intestinal absorption) along with 20

other aminos, they are used to make various proteins. This also moderates the

rise in blood glutamate/aspartate levels. Yet when the single amino MSG is

rapidly absorbed (especially in solution - e.g. soups, sauces and gravies), not

requiring digestion, human and animal experiments show rapid rises in glutamate,

5 to 20 times normal blood levels (2). Aspartame is a dipeptide - a union of 2

aminos- and there exist special di-and tripeptide intestinal absorption pathways

that allow rapid and efficient absorption (21). The dipeptides are then

separated into free aminos, and as with free MSG there will be a rapid rise in

blood aspartate. Thus the characteristics of food-bound glutamate/aspartate and

MSG/aspartame are completely different. The phenomenon of excitotoxicity can

occur even if you never use MSG/aspartame, since neurons can produce their own

glutamate/aspartate.

Nonetheless, given the danger of even slight rises in synaptic

glutamate/aspartate levels, prudence dictates that dietary MSG/aspartame be

avoided whenever possible, especially if you fall into the category of those

with weakened blood-brain barrier previously mentioned - diabetes, stroke

victims, Alzheimer's patients, etc. And once you begin reading food labels,

watching out not only for MSG/aspartame, but also for " hydrolysed vegetable

protein, " " natural flavor, " " spice, " " caseinate digest, " " yeast extract, " etc.,

you will be amazed at how common MSG and aspartame are in the modern food

supply.

EXCITOTOXICITY: STEALTH DEVELOPMENT

It should be emphasized that excitotoxicity can occur in both acute

and chronic (slowly developing) forms. NMDA channel blockers such as nimodipine

and memantine have shown success in blocking the dramatic change that occurs

rapidly after acute excitotoxicity reactions, as in stroke, asphyxia (lack of

oxygen), or head/spinal trauma (2,3,12). The chronic forms of excitotoxic brain

injury will usually occur much more slowly, and the effects may be subtle until

the final stage of the damage. For example, Parkinson's disease symptoms may not

show up until 80% or more of the nigrostriatal neurons are destroyed, a

partially excitotoxic process that may proceed " silently " for decades before

symptoms present themselves (2).

Similarly, excitotoxin pioneer Olney has recently shown that there

is a long, slow development of excitotoxic brain damage in Alzheimer's disease

that occurs before the dramatic Alzheimer's symptoms of memory loss,

disorientation, cognitive impairment, and emotional lability arise (10). So you

must not assume that just because you don't notice any obvious symptoms when you

consume MSG/aspartame -containing foods, there is no excitotoxic damage

occurring.

EXCITOTOXICITY PROTECTION: THE PROGRAM

As mentioned previously, there are 5 main background factors that

promote the transition of glutamate/aspartate from neurotransmitters to

excitotoxins. These will now be examined, since they provide the rationale for a

program of nutritional supplements/ life extension drugs to combat

excitotoxicity.

1) Inadequate neuronal ATP levels. This factor is one of the 2 chief

keys to preventing excitotoxicity. ATP is the energy " currency " of all cells,

including neurons. Each neuron must produce all the ATP it needs - there is no

welfare state to take care of needy but helpless neurons. ATP is needed to pump

glutamate out of the synaptic gap into either the glutamate-secreting neuron or

into astrocytes. ATP is needed by atrocytes to convert glutamate into

glutamine. ATP is needed by sodium and calcium pumps to get excess sodium and

calcium back out of the neuron after neuron firing. ATP is needed to maintain

neuron resting electric potential, which in turn maintains the magnesium-block

of the glutamate-NMDA receptor. With enough ATP bioenergy, neurons can keep

glutamate and aspartate in their proper role as neurotransmitters.

Neurons produce ATP by " burning " glucose (blood sugar) through 3

interlocking cellular cycles: the glycolytic and Krebs' cycles, and the electron

transport chain, with most of the ATP coming from the electron transport chain

(22). Various enzyme assemblies produce ATP from glucose through these 3

cycles, with the Krebs' cycle and electron transport chain occurring inside

mitochondria, the power plants of the cell. The various enzyme assemblies

require vitamins B1, B2, B3 (NADH), B5 (pantothenate), biotin, and alpha-lipoic

acid as coenzyme " spark plugs " (22). Magnesium is also required by most of the

glycolytic and Krebs' cycle enzymes as a mineral co-factor (22). The electron

transport chain especially relies on NADH and coenzyme Q10 (Co Q10) to generate

the bulk of the cell's ATP (22). Supplementary sublingual ATP, by supplying

preformed adenosine to cells, can also help in ATP (adenosine triphosphate)

formation (22). Idebenone is a synthetic variant of Co Q10 that may work better

than CoQ10, especially in low oxygen conditions, to keep ATP production going in

the electron transport chain (22). Acetyl l-carnitine is a natural

mitochondrial molecule that may regenerate aging mitochondria that are suffering

from a lifetime of accumulatedfree radical damage (22). Thus the basic

pro-energy anti-excitotoxic program consists of 50-100 mg of B1, B2, B3, B5;

500-10,000 mcg of biotin; 100-300 mg alpha-lipoic acid; 50-300 mg CoQ10; 45-90

mg Idebenone; 10-30 mg sublingual ATP; 500-2000 mg acetyl l-carnitine; and

300-600 mg Magnesium; and 5-20 mg NADH. All should be taken in divided doses

with meals, except the NADH, which is taken on an empty stomach.

2) Inadequate neuronal levels of magnesium. Magnesium is nature's

non-drug NMDA channel blocker. Magnesium is also essential, as just mentioned,

for ATP production, and the small amount of ATP that can be stored in cells is

stored as MgATP. Magnesium injections are routinely given to alcoholics going

through extreme withdrawal symptoms (delerium tremens), and alcohol withdrawal

is an excitotoxic process (11). Magnesium dietary levels in Western countries

are typically only 175-275mg/day (23). Dr Mildred Seelig, a noted magnesium

expert, has calculated that a minimum of 8 mg of magnesium/Kg of bodyweight are

needed to prevent cellular magnesium deficiency (24). This would be 560 mg/day

for a 70 kg (154 pound) person. Alcoholics, chronic diuretic users, diabetics,

candidiasis patients, and those under extreme, prolonged stress may need even

more (25). 300-600 mg magnesium per day, taken with food in divided doses,

should be adequate for healthy persons. Excess magnesium will cause diarrhoea;

reduce dose accordingly if necessary. Magnesium malate, succinate, glycinate,

ascorbate, chloride and taurinate are the best supplemental forms.

3) High neuronal levels of inflammatory prostaglandins (PG),

thromboxanes (TX) and leukotrienes (LT). The excitotoxic process does much of

its damage through initiating excessive production of prostaglandins,

thromboxanes, and leukotrienes. Inflammatory prostaglandins and thromboxanes are

produced by the action of cyclooxygenase 2 (COX-2) on arachidonic acid liberated

from cell membranes (16,26). Leukotrienes are produced by lipoxygenases (LOX)

(16). Trans-resveratrol is a powerful natural inhibitor of both COX-2 and LOX

(26,27,28). The bioflavonoid quercetin is a powerful LOX-inhibitor (27).

Curcumin (turmeric extract), rosemary extract, green tea extract, ginger and

oregano are also effective natural COX-2 inhibitors (26). It is interesting to

note that Alzheimer's disease is in large part an excitotoxicity disease (2,10),

and 20 epidemiological studies published by 1998 indicate that populations

taking anti-inflammatory drugs (e.g. arthritis sufferers) have a significantly

reduced prevalence of Alzheimer's disease or a slower mental decline (26).

However, both steroidal and non-steroidal anti-inflammatory drugs have

potentially dangerous side effects, so the natural anti-inflammatory substances

may be a much safer, if slightly less powerful, alternative. 5-20 mg

trans-resveratrol 2-3 times daily, 250-500 mg quercetin 3 times daily, and

300-600 mg rosemary extract 2-3 times daily is a safe, natural anti-inflammatory

program.

4) Excessive free radical formation/inadequate antioxidant status

is a major pathway of excitotoxic damage. Various free radicals, including

superoxide, peroxide, hydroxyl and peroxynitrite, are generated through the

inflammatory prostaglandin/leukotriene pathways triggered by excitotoxic

intracellular calcium excess. These free radicals can damage or destroy

virtually every cellular biomolecule: proteins, fatty acids, phospholipids,

glycoproteins, even DNA, leading to cell injury or death (1-3, 16, 17). Free

radicals are also inevitably formed whenever mitochondria produce ATP (22).

Reduced intraneuronal antioxidant defenses is a routine finding in autopsy

studies of brains from Alzheimer's and Parkinson's patients (2). Although

vitamins C and E are the two most important nutritional antioxidants, and brain

cells may concentrate C to levels 100 times higher than blood levels (30),

antioxidants work as a team. Free radical researcher Lester Packer has

identified C, E, alpha-lipoic acid, Co Q10 and NADH as the most important

dietary antioxidants (31,32) Idebenone has also shown great power in protecting

various types of neurons from free radical damage and other excitotoxic effects.

Idebenone is able to protect neurons at levels 30-100 times less than the

vitamin E levels needed to protect neurons from excitotoxic damage (33-37). One

of the many ways excitotoxins damage neurons is to prevent the intracellular

formation of glutathione, one of the most important cellular antioxidants. The

combination of E and Idebenone provided complete antioxidant neuronal protection

in spite of extremely low glutathione levels caused by glutamate excitotoxic

action (33,34). Idebenone has also shown clinical effectiveness in treating

various forms of stroke and cerebrovascular dementia, known to be caused by

excitotoxic damage (38).

Deprenyl is also indicated for prevention of excitotoxic free

radical damage. In a recent study, Mytilneou and colleagues showed that deprenyl

protected mesencephalic dopamine neurons from NMDA excitotoxicity comparably to

the standard NMDA blocker, MK-801 (39). The chief bodily metabolite of deprenyl,

desmethylselegeline, was shown to be even more powerful than deprenyl itself at

preventing NMDA excitotoxic damage to dopamine neurons (40). Maruyama and

colleagues showed that deprenyl protected human doparminergic cells from

apoptosis (cell suicide) induced by peroxynitrite, a free radical generated

through NMDA excitotoxic action (3,17). Deprenyl has also been shown to

significantly increase the activity of 2 key antioxidant enzymes, superoxide

dismutase (SOD) and catalase, in rat brain (41). There is also good evidence

that deprenyl, through its MAO-B inhibiting action, may favorably modulate the

polyamine binding site on NMDA receptors, thereby reducing excitotoxicity (41).

A basic anti-excitotoxic antioxidant program would thus consist of the

following: 200-400 IU d-alpha tocopherol; 100-200 mg gamma tocopherol (this form

of vitamin E has recently been shown to be highly protective against

peroxynitrite toxicity, unlike d-alpha E (42); 100-200 mcg selenium as

selenomethionine (selenium is necessary for the activity of glutathione

peroxidase, one of the most critical intracellular antioxidants); 500-1,000 mg

vitamin C 3-5 times daily; 50-100 mg alpha-lipoic acid 2-3 times daily; 50-300mg

Co Q10; 5-20 mg NADH (empty stomach); 45 mg Idebenone 2 times daily; 1.5-2 mg

deprenyl daily. Note that some of these are already covered by the energy

enhancement program.

Zinc is necessary for one form of SOD - zinc SOD - and also blocks

the NMDA receptor. However, high levels of neuronal zinc may over activate the

quisqualate/AMPA glutamate receptors, causing an excitotoxic action. (1,2) Dr

Blaylock, the neurosurgeon author of Excitotoxins (2), therefore recommends

keeping supplementary zinc levels to 10-20 mg daily. (2)

5) Inadequate removal of extracellular (synaptic) glutamate.

Excessive synaptic glutamate/aspartate will keep glutamate receptors

(NMDA or non-NMDA) overactive, promoting repetitive neuronal electrical firing,

calcium/sodium influx, and resultant excitotoxicity. Avoiding dietary

MSG/aspartame will help to minimize synaptic glutamate/aspartate levels. Keeping

neuronal ATP energy maximal through avoidance of hypoglycemia (i.e. don't skip

meals or practice " starvation dieting " ), combined with the supplemental energy

program described in 1) above, will promote adequate ATP to assist glutamate

pumps to remove excess extracellular glutamate to astrocytes. Adequate ATP will

also promote astrocyte conversion of glutamate to glutamine, the chief glutamate

removal mechanism. Adequate ATP will also keep calcium and sodium pumps active,

preventing excessive intracellular calcium build-up. Intracellular calcium

excess itself promotes renewed secretion of glutamate into synapses, in a

positive feedback vicious cycle (3).

An enzyme called " glutamate dehydrogenase " also helps neurons

dispose of excess glutamate by converting glutamate to alpha-ketoglutarate, a

Krebs' cycle fuel. Glutamate dehydrogenase is activated by NADH, so taking the

NADH recommended in the energy and antioxidant programs will also promote

breakdown of glutamate excess. Excessive levels of free radicals has been shown

to inhibit glutamate uptake by astrocytes, the major route for terminating

glutamate receptor activation (29), so following the antioxidant program will

also aid in clearing excess synaptic glutamate. In order to maximize clearance

of synaptic glutamate, it will also be necessary to avoid use of the nutritional

supplement glutamine. The health food industry has promoted glutamine use for

decades, often in multi-gram quantities. A 1994 book touts glutamine " to

strengthen the immune system, improve muscle mass, and heal the digestive tract "

(43). It is true that many studies do show benefits form short-term, often high

dose, glutamine use. It must be remembered, however, that glutamine easily

passes the blood-brain barrier and enters the astrocytes and neurons, where it

can be converted to glutamate. And the excitotoxic damage from excess glutamate

may take a lifetime to develop to the point of expressing itself as a stroke,

Alzheimer's or Parkinson's disease, etc. But high dose glutamine can cause

excitotoxic problems even in the short term. At last year's Monte Carlo

Anti-Aging Conference, I met a man who routinely consumed 20 grams of glutamine

daily. He suffered extremely severe insomnia, nervousness, anxiety, racing

mind, and other symptoms of excessive glutamate neurotransmission. glutamine

supplementation should probably not exceed 1-2 grams daily, if it is used at

all.

EXCITOTOXINS: FINAL THOUGHTS & OBSERVATIONS

A 1994 review article referred to excitotoxicity as " the final

common pathway for neurologic disorders " .(3) Yet public awareness of the

excitotoxic phenomenon has been slow in coming, even in the life

extension/natural medicine/health food communities. Only one book has tried to

alert the public to the details of how excitotoxins gradually (or sometimes

suddenly) destroy our brains: Blaylock's 1994/1997 Excitotoxins (2). This

article has barely scratched the surface of excitotoxins and their role in our

lives. The interested reader is strongly urged to read Blaylock's book. It is

written by a neurosurgeon, is highly readable and understandable for such a

technical subject, and provides a wealth of practical information and extensive

scientific documentation. Blaylock presents an especially detailed picture of

the role of glutamate/aspartate excitotoxicity in the development of Alzheimer's

disease, as well as steps to prevent or cope with Alzheimer's. It makes little

sense to pursue other anti-aging strategies, such as growth hormone,

testosterone or estrogen replacement, cardiovascular fitness exercise, weight

loss, etc. while not doing everything possible to avoid excitotoxicity. As

Blaylock points out, in a recent survey of the elderly, it was learned that the

incidence of Alzheimer's was 3% among the 65 to 74 age group, 18.7% among those

75 to 84, and 47.2% (!) among those 85 and older (2). The over-85 age group is

the fastest growing .age group in the U.S. Anyone who seriously follows the

anti-aging techniques promoted by IAS has a real chance of joining that 85-plus

age group. But what is the point of reaching 85, only to end up suffering the

terrible physical, mental and emotional deterioration of Alzheimer's (or

Parkinson's, or stroke dementia, etc.)? Learning about, and doing what is

necessary to cope with, the brain's tendency to excitotoxically " melt down " is

the best brain anti-aging insurance available.

REFERENCES

1) Choi, D. (1988) " Glutamate neurotoxicity and diseases of the

nervous system " Neuron 1: 623-34.

2) Blaylock, R. Excitotoxins. Santa Fe: Health Press, 1997.

3) Lipton, S. & Rosenberg, P. (1994) " Excitatory amino acids as a

final common pathway for neurologic disorders " NEJM 330: 613-22.

4) Greenamyre, J. & Porter, R. (1994) " Anatomy and physiology of

glutamate in the CNS " Neurol 44: s7-sl3.

5) Braverman, E. et al. The Healing Nutrients Within. New Canaan:

Keats Pub., 1997.

6) , H. Aspartame (NutraSweet®) Is It Safe? Philadelphia: The

Press, 1990.

7) Blaylock. R. (2000) " Excitotoxins: Dangerous Food Additives "

Nexus 7 (#4 & 5), 31-34,74-75 & 35-40.

8) Whetsell,W. & Shapira, N. (1993) " Biology of disease.

Neuroexcitation, excitotoxicity and human neurological disease. " Lab Invest 68:

372-87.

9) Olney, J. (1989) " Glutamate, a neurotoxic transmitter " J Child

Neurol 4:218-26.

10) Olney, J. et al (1997) " Excitotoxic neurodegeneration in

Alzheimer's disease " Arch Neurol 54:1234-40.

11) Tsai, G.E. et al (1998) " Increased glutamatergic

neurotransmission and oxidative stress after alcohol withdrawal " Am J Psychiat

155: 726-32.

12) (2001) " Needless brain wasting " Life Extension 7 (7): 64-68.

13) Blaylock, Excitotoxins, p.49.

14) Levitan, 1. & Kaczmarek. The Neuron. NY & Oxford: Oxford Univ.

Press, 1997.

15) Guyton, A. & Hall, J. Textbook of Medical Physiology.

Philadelphia: W.B. Saunders, 2000.

16) Levine, S. & Kidd, P. Antioxidant Adaptation. S.F. Biocurrents,

1986.

17) Maroyama, W. et al (1998) " Deprenyl protects human dopaminergic

neuroblastoma ...cells from apoptosis induced by peroxynitrite and nitric oxide "

J Neuronchem 70: 2510-15.

18) Sorg, 0. et al (1997) " Inhibition of astrocyte glutamate uptake

by reactive oxygen species: role of antioxidant enzymes " Mol. Med 7: 431-40.

19) Pol, A. et al (1990) " Glutamate, the dominant excitatory

transmitter in neuroendocrine regulation " Sci 250: 1276-78.

20) Toth, E. & Lajtha, A. (1981) " Elevation of cerebral levels on

nonessential amino acids in vivo by administration of large doses " Neurochem Res

6:1309-17.

21) Zaioga, G. (1990) " Physiologic effects of peptide-based enteral

formulas " Nutr Clin Pract 5:231-37.

22) South, J. (1999) " Tired of being tired? " Anti-Aging Bull 4(4):

3-21.

23) Wester, p.o. (1987) " Magnesium " Am J Clin Nutr 45: 1305-12.

24) Seelig, M. (1964) " Perspectives in nutrition. The requirement of

magnesium by the normal adult " Am J Clin Nutr 14: 342-90.

25) South, J. (1990) " Magnesium: the missing link to health " Opt

Nutr Rev 1:1,5-8.

26) Newmark, T. & Schulick, P. Beyond Aspirin. Prescott A2: Hohm

Press, 2000.

27) Pace- Asciak. C. el al (1995) " The red wine phenolics

trans-resveratrol and quercetin block human platelet aggregation and eicosanoid

synthesis: Implications for protection against coronary heart disease " Clin Chem

Acta 235: 207-19.

28) Kimura, Y. et al (1985) " Effects of stilbenes on arachidonate

metabolism in leukocytes " Biochim Biophys Acta 834: 275-78.

29) Same as ref. 18.

30) Grunewald, R. (1993) " Ascorbic acid in the brain " Brain Res Rev

18: 123-33.

31) Packer, L. & Colman, C. The Antioxidant Miracle.' NYC:

Wiley, 1999.

32) Packer, L. Tritschler, H. (1996) " Alpha-lipoic acid: the

metabolic antioxidant " Free Rad Biol Med 20: 625-26.

33) Oka, A. et al (1993) " Vulnerability of oligodendroglia to

glutamate: pharmacology, mechanisms and protection " J Neurosci 13: 1441-53.

34) , T. et al (1990) " Immature cortical neurons are uniquely

sensitive to glutamate toxicity by inhibition of cystine uptake " FASEB J 4:

1624-33.

35) Miyamoto, M. & Coyle, J. (1990) " Idebenone attenuates neuronal

degeneration induced by intrastriatal injection of excitotoxins " Exp Neurol 108:

38-45.

36) Miyamoto, M. et al (1989) " Antioxidants protect against

glutamate-induced cytotoxicity in a neuronal cell line " J Pharmacol Exp Ther

250: 1132-40.

37) Bruno, V. et al (1994) " Protective action of idebenone against

excitotoxic degeneration in cultured cortical neurons " Neurosci Lett 178:

193-96.

38) Sekimoto, H. et al (1985) " Efficacy and safety of CV-2619

(idebenone) in multiple cerebral infarction, cerebrovascular dementia, and

senile dementia " Ther Res 2:957-72.

39) Mytilineou, C. et al (1997) " L-Deprenyl protects mesencephalic

dopamine neurons from glutamate receptor-mediated toxicity in vitro " J Neurochem

68: 33-39.

40) Mytilineou, C. et al (1997) " L-(-)-Desmethylselegeline, a

metabolite of selegeline (L-(-)-deprenyl, protects mesencephalic dopamine

neurons from excitotoxicity in vitro " J Neurochem 68:434-36.

41) Knoll, J (1986) " Pharmacology of selegeline " J Neural Transm

Suppl 1986; 22:75-89..

42) Christen, S. et al (1997) " Gamma-tocopherol traps mutagenic

electrophiles such as NO(X) and complements alpha tocopherol: physiologic

implications " Proc Nati Acad Sci USA 94: 3217-22.

43) Shabert. J. & Ehriich, N. The Ultimate Nutrient Glutamine.

Garden City Park. NY: Avery, 1994.

ALL INFORMATION IS EDUCATIONAL AND SHOULD NOT REPLACE THE ADVICE OF

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