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.