Excitotoxins - the ultimate brainslayer

[Guest guest]

Excitotoxins - 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. (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). (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.

http://smart-drugs.net/ias-excitotoxins.htm

 

ALL INFORMATION IS EDUCATIONAL AND SHOULD NOT REPLACE THE ADVICE OF YOUR

PHYSICIAN.

_________________

_________________

JoAnn Guest

mrsjoguest

DietaryTipsForHBP

www.geocities.com/mrsjoguest/Genes

 

 

 

 

AIM Barleygreen

" Wisdom of the Past, Food of the Future "

 

http://www.geocities.com/mrsjoguest/Diets.html