Excitotoxins - The ultimate Brainslayer

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Excito. toxins - The ultimate Brainslayer

 

by James 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.

 

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.

 

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). (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 (1. (1. (1.

 

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. John 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.

(

 

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) (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

(26,27,2.

 

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 (3.

 

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

Charles Press, 1990.

 

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

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

 

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.

 

1 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.

 

2 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: John 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) Murphy, 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.

 

3 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.

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