Excitotoxins, Neurodegeneration & Neurodevelopment

[Guest guest]

Excitotoxins, Neurodegeneration and Neurodevelopment JoAnn Guest Jul 21,

2003 14:13 PDT

 

Excitotoxins, Neurodegeneration and Neurodevelopment

by Russell L. Blaylock, M.D.

 

There are a growing number of clinicians and basic scientists who

are convinced that a group of compounds called " excitotoxins " play a

critical role in the development of several neurological disorders

including migraines, seizures, infections, abnormal neural development,

certain endocrine disorders, neuropsychiatric disorders, learning

disorders in children, AIDS dementia, episodic violence, lyme

borreliosis, hepatic encephalopathy, specific types of obesity, and

especially the neurodegenerative diseases, such as ALS, Parkinson's

disease, Alzheimer's disease, Huntington's disease, and

olivopontocerebellar degeneration.

 

An enormous amount of both clinical and experimental evidence has

accumulated over the past decade supporting this basic premise.

Yet, the FDA still refuses to recognize the immediate and long

termdanger to the public caused by the practice of allowing various

excitotoxins to be added to the food supply,

 

such as MSG, hydrolyzed vegetable protein, and

aspartame.

 

The amount of these neurotoxins added to our food has

increased enormously since their first introduction. For example, since

1948 the amount of MSG added to foods has doubled every decade.

 

By 1972 262,000 metric tons were being added to foods. Over 800 million

pounds of aspartame have been consumed in various products since it was

first approved.

 

Ironically, these food additives have nothing to do with

preserving food or protecting its integrity. They are all used to alter

the taste of food.

 

MSG, hydrolyzed vegetable protein, and natural

flavoring are used to enhance the taste of food so that it tastes

better.

 

Aspartame is an artificial sweetener.

 

These toxins (excitotoxins) are not present in just a few foods,

but rather in almost all processed foods.

 

In many cases they are being added in disguised forms, such as " natural "

flavoring, " spices " , " yeast

extract " , " textured protein " , soy protein extract, etc.

 

Experimentally, we know that when subtoxic levels of excitotoxins are

given to animals in divided doses, they experience full toxicity,

i.e.they are synergistic.

 

Also, liquid forms of excitotoxins, as occurs in soups, gravies and diet

soft drinks are more toxic than that added to solid foods. This is

because they are more rapidly absorbed and reach higher blood levels.

 

So, what is an excitotoxin?

These are substances, usually acidic amino acids, that react with

specialized receptors in the brain in such a way as to lead to

destruction of certain types of neurons.

 

Glutamate is one of the more commonly known excitotoxins. MSG is the

sodium salt of glutamate.

 

This amino acid is a normal neurotransmitter in the brain.

In fact, it is the most commonly used neurotransmitter by the brain.

Defenders of MSG and aspartame use, usually say:

 

How could a substance that is used normally by the brain cause harm?

 

This is because, glutamate, as a neurotransmitter, exists in the

extracellular fluid only in very, very small concentrations - no more

than 8 to 12uM.

 

When the concentration of this transmitter rises above this level the

neurons begin to *fire* abnormally.

 

At higher concentrations, the cells undergo a

specialized process of delayed cell death known as excitotoxicity, that

is, they are " excited " to *death*.

 

It should also be appreciated that the effects of excitotoxin food

additives generally are not dramatic. Some individuals may be especially

sensitive and develop severe symptoms and even sudden death from cardiac

irritability,

 

but in most instances the effects are subtle and develop

over a long period of time.

 

While the food additives, MSG and aspartame, are probably not direct

causes of the neurodegenerative diseases, such

as Alzheimer's dementia, Parkinson's disease, or amyotrophic lateral

sclerosis, they may well precipitate these disorders and certainly

worsen their pathology as we shall see.

 

It may be that many people with a propensity for developing one of

these diseases would never develop a full blown disorder had it not been

for their exposure to high levels of

food borne excitotoxin additives.

 

Some may have had a very mild form of the disease had it not been for

the exposure.

 

Likewise, food borne excitotoxins may be harmful to those suffering

from strokes, head injury and HIV infection and certainly should not be

used in a hospital setting.

 

How Excitotoxins Were Discovered

 

In 1957, two opthalmology residents, Lucas and Newhouse, were

conducting an experiment on mice to study a particular eye disorder.

 

During the course of this experiment they fed newborn mice MSG and

discovered that all demonstrated widespread destruction of the inner

nerve layer of the retina.

 

Similar destruction was also seen in adult mice but not as severe as

the newborns.

The results of their experiment was published in the Archives of

Opthalmology and soon forgotten.

 

For ten years prior to this report, large amounts of MSG were being

added not only to adult foods but also to baby foods in doses equal to

those of the experimental animals.

 

Then in 1969, Dr. John Olney, a neuroscientist and

neuropathologist working out of the Department of Psychiatry at

Washington University in St. Louis, repeated Lucas and Newhouse's

experiment.

 

His lab assistant noticed that the newborn of MSG exposed

mice were grossly obese and short in statue.

 

Further examination also demonstrated hypoplastic organs, including

pituitary, thyroid, adrenal as well as reproductive dysfunction.

Physiologically, they demonstrated multiple endocrine deficiencies,

including TSH, growth hormone, LH, FSH,

and ACTH.

 

When Dr. Olney examined the animal's brain, he discovered

discrete lesions of the arcuate nucleus as well as less severe

destruction of other hypothalamic nuclei.

 

Recent studies have shown that glutamate is the most important

neurotransmitter in the hypothalamus.

 

Since this early observation, monosodium glutamate and other excitatory

substances have become the standard tool in studying the function of the

hypothalamus.

 

Later studies indicated that the damage by monosodium

glutamate was much more widespread, including the hippocampus,

circumventricular organs, locus cereulus, amygdala- limbic system,

subthalamus, and striatum.

 

More recent molecular studies have disclosed the mechanism of this

destruction in some detail.

 

Early on it was observed that when neurons in vitro were exposed to

glutamate and then washed clean, the cells appeared perfectly normal for

approximately an hour, at which time

they rapidly underwent cell death.

 

It was discovered that when calcium was removed from the medium, the

cells continued to survive.

 

Subsequent studies have shown that glutamate, and other excitatory

amino acids, attach to a specialized family of receptors ( NMDA,

kainate, AMPA and metabotrophic) which in turn, either directly or

indirectly, opens the

calcium channel on the neuron cell membrane, allowing calcium to flood

into the cell.

 

If unchecked, this calcium will trigger a cascade of

reactions,

 

including free radical generation, eicosanoid production, and

lipid peroxidation, which will destroy the cell.

 

With this calcium triggered stimulation, the neuron becomes very

excited, firing its impulses repetitively until the point of cell death,

hence the name excitotoxin.

 

The activation of the calcium channel via the NMDA type

receptors also involves other membrane receptors such as the zinc,

magnesium, phencyclidine, and glycine receptors

 

 

 

In many disorders connected to excitotoxicity, the source of the

glutamate and aspartate is indogenous.

 

We know that when brain cells are injured they release large amounts of

glutamate from surrounding

astrocytes, and this glutamate can further damage surrounding normal

neuronal cells.

 

This appears to be the case in strokes, seizures and

brain trauma. But, food born excitotoxins can add significantly to this

accumulation of toxins.

 

The FDA's Response

 

In July, 1995 the Federation of American Societies for

Experimental Biology ( FASEB) conducted a definitive study for the FDA

on the question of safety of MSG.

 

The FDA wrote a very deceptive summary of the report in which they

implied that, except possibly for asthma patients, MSG was found to be

safe by the FASEB reviewers.

 

But, in fact, that is not what the report said at all. I summarized, in

detail, my criticism of this widely reported FDA deception in the

revised paperback edition of my book, Excitotoxins: The Taste That

Kills, by analyzing exactly what the report said, and failed to say.

 

For example, it never said that MSG did not aggravate neurodegenerative

diseases.

 

What they said was, there were no studies indicating such a

link. Specifically, that no one has conducted any studies, positive or

negative, to see if there is a link. A vital difference.

 

Unfortunately, for the consumer, the corporate food processors not

only continue to add MSG to our foods but they have gone to great

lengths to disguise these harmful additives.

 

For example, they use such names as hydrolyzed vegetable protein,

vegetable protein, textured protein,

hydrolyzed plant protein, soy protein extract, caseinate, yeast extract,

and natural flavoring.

 

We know experimentally that when these

excitotoxin taste enhancers are added together they become much more

toxic than is seen individually.

 

In fact, excitotoxins in subtoxic concentrations can be fully toxic

to specialized brain cells when used in combination.

 

Frequently, I see processed foods on supermarket

shelves, especially frozen or diet foods, that contain two, three or

even four types of excitotoxins.

 

We also know, as stated, that excitotoxins in liquid forms are much

more toxic than solid forms because they are rapidly absorbed and attain

high concentration in the blood.

 

This means that many of the commercial soups, sauces, and gravies

containing MSG are very dangerous to nervous system health, and should

especially be avoided by those either having one of the above mentioned

disorders, or who are at a high risk of developing one of them. They

should also be avoided by cancer patients and those at high risk for

cancer, because of the associated generation of free radicals and lipid

peroxidation.

 

In the case of ALS, amyotrophic lateral sclerosis, we know that

consumption of red meats and especially MSG itself, can significantly

elevate blood glutamate, much higher than is seen in the normal

population.

 

Similar studies, as far as I am aware, have not been

conducted in patients with Alzheimer's disease or Parkinson's disease.

But, as a general rule I would certainly suggest that person's with

either of these diseases avoid MSG containing foods as well as red

meats, cheeses, and pureed tomatoes,

 

all of which are known to have

higher levels of glutamate.

 

It must be remembered that it is the glutamate molecule that is

toxic in MSG ( monosodium glutamate). Glutamate is a naturally occurring

amino acid found in varying concentrations in many foods. Defenders of

MSG safety allude to this fact in their defense. But, it is free

glutamate that is the culprit.

 

Bound glutamate, found naturally in foods, is less dangerous because it

is slowly broken down and absorbed by the gut, so that it can be

utilized by the tissues, especially

muscle, before toxic concentrations can build up.

 

Therefore, a whole tomato is safer than a pureed tomato. The only

exception to this as

stated, based on present knowledge, is in the case of ALS.

 

Also, the tomato plant contains several powerful antioxidants known to

block glutamate toxicity.

 

Hydrolyzed vegetable protein is a common food additive and may

contain at least two excitotoxins, glutamate and cysteic acid.

Hydrolyzed vegetable protein is made by a chemical process that breaks

down the vegetable's protein structure to purposefully free the

glutamate, as well as aspartate, another excitotoxin.

 

This brown powdery substance is used to enhance the flavor of foods,

especially meat dishes, soups, and sauces. Despite the fact that some

health food

manufacturers have attempted to sell the idea that this flavor enhancer

is " all natural " and " safe " because it is made from vegetables, it is

not.

 

It is the same substance added to processed foods. Experimentally,

one can produce the same brain lesions using hydrolyzed vegetable

protein as by using MSG or aspartate.

 

A growing list of excitotoxins are being discovered, including

several that are found naturally.

 

For example, L- cysteine is a very

powerful excitotoxin. Recently, it has been added to certain bread dough

and is sold in health food stores as a supplement.

 

 

Homocysteine, a metabolic derivative, is also an excitotoxin.

 

Interestingly, elevated blood levels of homocysteine has recently

been shown to be a major, if not the major, indicator of cardiovascular

disease and stroke.

 

Equally interesting, is the finding that elevated levels have also been

implicated in neurodevelopmental disorders, especially anencephaly and

spinal dysraphism ( neural tube defects).

 

It is thought that this is the protective mechanism of action

associated with the use of the

prenatal vitamins B12, B6, and folate when used in combination. It

remains to be seen if the toxic effect is excitatory or by some other

mechanism.

 

If it is excitatory, then unborn infants would be endangered

as well by glutamate, aspartate ( part of the aspartame molecule), and

the other excitotoxins. Recently, several studies have been done in

which it was found that all Alzheimer's patients examined had elevated

levels of homocysteine.

 

One interesting study found that persons affected by Alzheimer's

disease also have widespread destruction of their retinal ganglion

cells.

 

Interestingly, this is the area found to be affected when

Lucas and Newhouse first discovered the excitotoxicity of MSG. While

this does not prove that dietary glutamate and other excitotoxins cause

or aggravate Alzheimer's disease, it is powerful circumstantial

evidence.

 

When all of the information known concerning excitatory food

additives is analyzed, it is hard to justify continued approval by the

FDA for the widespread use of these food additives.

 

The Free Radical Connection

 

It is interesting to note that many of the same neurological

diseases associated with excitotoxic injury are also associated with

accumulations of toxic free radicals and destructive lipid oxidation

products.

For example, the brains of Alzheimer's disease patients

have been found to contain high concentration of lipid peroxidation

products and evidence of free radical accumulation and damage.

 

 

In the case of Parkinson's disease, we know that one of the early

changes is the loss of one of the primary antioxidant defense systems,

glutathione, from the neurons of the striate system, and especially in

the substantia nigra.

 

It is this nucleus that is primarily affected in this disorder.

Accompanying this, is an accumulation of free iron,

which is one of the most powerful free radical generators known.

 

One of the highest concentrations of iron in the body is within the

globus pallidus and the substantia nigra. The neurons within the latter

are especially vulnerable to oxidant stress because the catabolic

metabolism of the transmitter-dopamine- can proceed to the creation of

very powerful free radicals.

 

That is, it can auto-oxidize to peroxide,which is

normally detoxified by glutathione.

 

As we have seen, glutathione loss in the substantia nigra is one of the

earliest deficiencies seen in

Parkinson's disease.

 

In the presence of high concentrations of free

iron, the peroxide is converted into the dangerous, and very powerful

free radical, hydroxide.

 

As the hydroxide radical diffuses throughout

the cell, destruction of the lipid components of the cell takes place, a

process called lipid peroxidation.

 

Of equal importance is the generation

of the powerful peroxynitrite radical, which has been shown to produce

serious injury to cellular proteins and DNA, both mitochondrial and

nuclear.

 

Using a laser microprobe mass analyzer, researchers have recently

discovered that iron accumulation in Parkinson's disease is primarily

localized in the neuromelanin granules ( which gives the nucleus its

black color).

It has also been shown that there is dramatic

accumulation of aluminum within these granules.

 

Most likely, the aluminum displaces the bound iron, releasing highly

reactive free iron.

 

It is known that even low concentrations of aluminum salts can enhance

iron-induced lipid peroxidation by almost an order of magnitude.

Further, direct infusion of iron into the substantia nigra nucleus in

rodents can induce a Parkinsonian syndrome, and a dose related decline

in dopamine. Recent studies indicate that individuals having Parkinson's

disease also have defective iron metabolism.

 

Another early finding in Parkinson's disease is the reduction in

complex I enzymes within the mitochondria of this nucleus. It is well

known that the complex I enzymes are particularly sensitive to free

radical injury.

 

These enzymes are critical to the production of cellular energy. As we

shall see, when cellular energy is decreased, the toxic effect of

excitatory amino acids increases dramatically.

 

In the case of ALS there is growing evidence that similar free

radical damage, most likely triggered by toxic concentrations of

excitotoxins, plays a major role in the disorder.

 

Several studies have demonstrated lipid peroxidation product

accumulation within the

spinal cords of ALS victims as well as iron accumulation.

 

It is now known that glutamate acts on its receptor via a nitric

oxide mechanism.

 

Overstimulation of the glutamate receptor can

produce an accumulation of reactive nitrogen species, resulting in the

generation of several species of dangerous free radicals, including

peroxynitrite. There is growing evidence that, at least in part, this is

how excess glutamate damages nerve cells.

 

In a multitude of studies,

a close link has been demonstrated between excitotoxicity and free

radical generation.

 

Others have shown that certain free radical scavengers

(antioxidants), have successfully blocked excitotoxic destruction of

neurons. For example, vitamin E is known to completely block glutamate

toxicity in vitro.

 

Whether it will be as efficient in vivo is not

known. But, it is interesting in light of the recent observations that

vitamin E combined with other antioxidant vitamins slows the course of

Alzheimer's disease and has been suggested to reduce the rate of advance

 

in a subgroup Parkinson's disease patients as well.

 

In the DATATOP study of the effect of alpha-tocopherol alone, no

reduction in disease progression was seen. The problem with this study

was the low dose that

was used and the fact that the DL-alpha-tocopherol used is known to have

a much lower antioxidant potency than D-alpha-tocopherol.

 

Stanley Fahn found that a combination of D-alpha-tocopherol and

ascorbic acid in high

doses reduced progression of the disease by 2.5 years.

 

Tocotrienol may have even greater benefits, especially when used in

combination with other antioxidants. There is some clinical evidence,

including my own observations, that vitamin E also slows the course of

ALS as well, especially in the form of D- alpha-tocopherol.

 

I would caution that

antioxidants work best in combination and when used separately can have

opposite, harmful, effects.

 

That is, when antioxidants, such as ascorbic

acid and alpha tocopherol, become oxidized themselves, such as in the

case of dehydroascorbic acid, they no longer protect, but rather act as

free radicals themselves.

 

The same is true of alpha-tocopherol.

 

Again, it should be realized that excessive glutamate stimulation

triggers a chain of events that in turn sparks the generation of large

numbers of free radical species, both as nitrogen and oxygen species.

 

 

These free radicals have been shown to damage cellular proteins (

protein carbonyl products) and DNA . The most immediate DNA damage is to

the mitochondrial DNA, which controls protein expression within that

particular cell and its progeny, producing rather profound changes in

cellular energy production.

 

It is suspected that at least some of the neurodegenerative diseases,

Parkinson's disease in particular, are affected in this way.

 

Chronic free radical accumulation would result

in an impaired functional reserve of antioxidant vitamins/minerals and

enzymes, and thiol compounds necessary for neural protection.

 

Chronic unrelieved stress, chronic infection, free radical generating

metals and toxins, and impaired DNA repair enzymes all add to this

damage.

 

We know that there are four main endogenous sources of oxidants:

 

1. Those produced naturally from aerobic metabolism of glucose.

 

2. Those produced during phagocytic cell attack on bacteria,

viruses, and parasites, especially with chronic infections.

 

3. Those produced during the degradation of fatty acids and other

molecules that produce h3O2 as a by-product. (This is important in

stress, which has been shown to significantly increase brain levels of

free radicals.) And

 

4. Oxidants produced during the course of p450 degradation of

natural toxins. And, as we have seen, one of the major endogenous

sources of free radicals is from the exposure of tissues to free iron,

especially in the presence of ascorbate.

 

Unfortunately, iron is one mineral heavily promoted by the health

industry, and is frequently added to many foods, especially breads and

pastas.

 

Copper is also a powerful free radical generator and has been shown to

be elevated within the substantia nigra of Parkinsonian brains.

 

What has been shown in all these studies is a direct connection

between excitotoxicity and free radical generation in a multitude of

diseases and disorders such as seizures, strokes, brain trauma,viral

infections, and neurodegenerative diseases.

 

Interestingly, free radicals have also been shown to prevent glutamate

uptake by astrocytes as well,

which would significantly increase extracellular glutamate levels

 

 

This creates a vicious cycle that will multiply any resulting damage and

malfunctioning of neurophysiological systems, such as plasticity.

 

The Blood-Brain Barrier

 

One of the MSG industry's chief arguments for the safety of their

product is that glutamate in the blood cannot enter the brain because of

the blood-brain barrier ( BBB), a system of specialized capillary

structures designed to exclude toxic substance from entering the brain.

 

 

There are several criticisms of their defense. For example, it is known

that the brain, even in the adult, has several areas that normally do

not have a barrier system, called the circumventricular organs.

 

These include the hypothalamus, the subfornical organ, organium

vasculosum, area postrema, pineal gland, and the subcommisural organ.

 

Of these, the most important is the hypothalamus, since it is the

controlling center for all neuroendocrine regulation, sleep wake cycles,

emotional control,

caloric intake regulation, immune system regulation and regulation of

the autonomic nervous system. As stated, glutamate is the most important

neurotransmitter in the hypothalamus.

 

Therefore, careful regulation of blood levels of glutamate is very

important, since high blood

concentrations of glutamate would be expected to increase hypothalamic

levels as well.

 

One of the earliest and most consistent findings with

exposure to MSG is damage to an area of the hypothalamus known as the

arcuate nucleus.

 

This small hypothalamic nucleus controls a multitude of

neuroendocrine functions, as well as being intimately connected to

several other hypothalamic nuclei.

 

It has also been demonstrated that

high concentrations of blood glutamate and aspartate ( from foods) can

enter the so-called " protected brain " by seeping through the unprotected

 

areas, such as the hypothalamus or other circumventricular organs.

 

Another interesting observation is that chronic elevations of

blood glutamate can even seep through the normal blood-brain barrier

when these high concentrations are maintained over a long period of

time.

 

This would be the situation seen when individuals consume, on

a daily basis, foods high in the excitotoxins - MSG, aspartame and

L-cysteine.

 

Most experiments cited by the defenders of MSG safety were

conducted to test the efficiency of the BBB acutely. In nature, except

in the case of metabolic dysfunction ( such as with ALS), glutamate and

aspartate levels are not normally elevated on a continuous basis.

 

 

Sustained elevations of these excitotoxins are peculiar to the modern

diet. ( and in the ancient diets of the Orientals, but not in as high a

concentration.)

 

An additional critical factor ignored by the defenders of

excitotoxin food safety is the fact that many people in a large

population have disorders known to alter the permeability of the

blood-brain barrier.

 

The list of conditions associated with barrier

disruption include: hypertension, diabetes, ministrokes, major strokes,

head trauma, multiple sclerosis, brain tumors, chemotherapy, radiation

treatments to the nervous system, collagen-vascular diseases ( lupus),

AIDS, brain infections, certain drugs, Alzheimer's disease, and as a

consequence of natural aging. There may be many other conditions also

associated with barrier disruption that are as yet not known.

 

When the barrier is dysfunctional due to one of these conditions,

brain levels of glutamate and aspartate reflect blood levels.

 

That is,

foods containing high concentrations of these excitotoxins will increase

brain concentrations to toxic levels as well.

 

Take for example, multiple sclerosis. We know that when a person with

MS has an exacerbation of

symptoms, the blood-brain barrier near the lesions breaks down, leaving

the surrounding brain vulnerable to excitotoxin entry from the blood,

i.e. the diet.

 

But, not only is the adjacent brain vulnerable, but

the openings act as points of entry, eventually exposing the entire

brain to potentially toxic levels of glutamate. Several clinicians have

remarked that their MS patients were made worse following exposure to

dietary excitotoxins.

 

 

I have seen this myself. It is logical to assume

that patients with the other neurodegenerative disorders, such as

Alzheimer's disease, Parkinson's disease, and ALS will be made worse on

diets high in excitotoxins.

 

Barrier disruption has been demonstrated in

the case of Alzheimer's disease.

 

Recently, it has been shown that not only can free radicals open

the blood-brain barrier, but excitotoxins can as well.

 

In fact, glutamate receptors have been demonstrated on the barrier

itself.

 

In a carefully designed experiment, researchers produced opening of

the blood-brain barrier using injected iron as a free radical generator.

 

When a powerful free radical scavenger (U-74006F) was used in this

model, opening of the barrier was significantly blocked.

 

But, the glutamate blocker MK-801 acted even more effectively to

protect the barrier. The authors of this study concluded that glutamate

appears to be an important regulator of brain capillary transport and

stability, and that overstimulation of NMDA ( glutamate) receptors on

the

blood-brain barrier appears to play an important role in breakdown of

the barrier system.

 

What this also means is that high levels of dietary

glutamate or aspartate may very well disrupt the normal blood-brain

barrier, thus allowing more glutamate to enter the brain, creating a

vicious cycle.

 

Relation to Cellular Energy Production

 

Excitotoxin damage is heavily dependent on the energy state of the

cell.

 

Cells with a normal energy generation systems are very resistant

to such toxicity. When cells are energy deficient, no matter the cause -

 

hypoxia, starvation, metabolic poisons, hypoglycemia - they become

infinitely more susceptible to excitotoxic injury or death. Even normal

concentrations of glutamate are toxic to energy deficient cells.

 

t is known that in many of the neurodegenerative disorders, neuron

energy deficiency often precedes the clinical onset of the disease by

years, if not decades.

 

This has been demonstrated in the case of

Huntington disease and Alzheimer's disease using the PET scanner, which

measures brain metabolism. In the case of Parkinson's disease, several

groups have demonstrated that one of the early deficits of the disorder

is an impaired energy production by the complex I group of enzymes

within the mitochondria of the substantia nigra.

 

Interestingly, it is known that the complex I system is very sensitive

to free radical damage.

 

Recently, it has been shown that when striatal neurons are exposed

to microinjected excitotoxins there is a dramatic, and rapid fall in

energy production by these neurons.

 

 

CoEnzyme Q10 has been shown, in this

model, to restore energy production but not to prevent cellular death.

 

 

But when combined with niacinamide, both cellular energy production and

neuron protection is seen.

 

I recommend for those with neurodegenerative disorders, a combination

of CoQ10, acetyl-L carnitine, niacinamide, riboflavin, methylcobalamin,

and thiamine.

 

One of the newer revelation of modern molecular biology, is the

discovery of mitochondrial diseases, of which cellular energy deficiency

is a hallmark.

 

In many of these disorders, significant clinical

improvement has been seen following a similar regimen of vitamins

combined with CoQ10 and L-carnitine

 

Acetyl L-carnitine enters the brain in higher concentrations and also

increases brain acetylcholine,

necessary for normal memory function. While these particular substances

have been found to significantly boost brain energy function they are

not alone in this important property.

 

Phosphotidyl serine, Ginkgo Biloba, vitamin B12, folate, magnesium,

Vitamin K and several others are also being shown to be important.

 

While mitochrondial dysfunction is important in explaining why

some are more vulnerable to excitotoxin damage than others, it does not

explain injury in those with normal cellular metabolism. There are

several conditions under which energy metabolism is impaired. We know,

for example, approximately one third of Americans suffer from reactive

hypoglycemia.

 

That is, they respond to a meal composed of either simple

sugars or carbohydrates (that are quickly broken down into simple

sugars, i.e. a high glycemic index.) by secreting excessive amounts of

insulin. This causes a dramatic lowering of the blood sugar.

 

When the blood sugar falls, the body responds by releasing a burst

of epinephrine from the adrenal glands, in an effort to raise the blood

sugar.

 

We feel this release as nervousness, palpitations of our heart,

tremulousness, and profuse sweating.

 

 

Occasionally, one can have a slower fall in the blood sugar that will

not produce a reactive release of

epinephrine, thereby producing few symptoms. This can be more dangerous,

since we are unaware that our glucose reserve is falling until we

develop obvious neurological symptoms, such as difficulty thinking and a

sensation of lightheadedness.

 

The brain is one of the most glucose dependent organs known, since

it has a limited ability to metabolize other substrates such as fats.

 

There is some evidence that several of the neurodegenerative diseases

are related to either excessive insulin release, as with Alzheimer's

disease, or impaired glucose utilization, as we have seen in the case of

 

Parkinson's disease and Huntington's disease.

 

It is my firm belief, based on clinical experience and

physiological principles, that many of these diseases occur primarily in

the face of either reactive hypoglycemia or " brain hypoglycemia " , a

condition where the blood sugar is normal and the brain is hypoglycemic

in isolation.

 

In at least two well conducted studies it was found that

pure Alzheimer's dementia was rare in those with normal blood sugar

profiles, and that in most cases Alzheimer's patients had low blood

sugars, and high CSF ( cerebrospinal fluid) insulin levels.

 

In my own limited experience with Parkinson's and ALS patients I have

found a

disproportionately high number suffering from reactive hypoglycemia.

 

I found it interesting that several ALS patients have observed an

association between their symptoms and gluten. That is, when they adhere

to a gluten free diet they improve clinically.

 

It may be that by avoiding gluten containing products, such as bread,

crackers, cereal, pasta ,etc, they are also avoiding products that are

high on the glycemic index, i.e. that produce reactive hypoglycemia.

 

Also, all of these food items are high in free iron. Clinically,

hypoglycemia will worsen the symptoms of most neurological disorders. We

know that severe hypoglycemia can, in fact, mimic ALS both clinically

and pathologically

 

It is also known that many of the symptoms of

Alzheimer's disease resemble hypoglycemia, as if the brain is

hypoglycemic in isolation.

 

In studies of animals exposed to repeated mild episodes of hypoxia

( lack of brain oxygenation), it was found that such accumulated

injuries can trigger biochemical changes that resemble those seen in

Alzheimer's patients.

 

One of the effects of hypoxia is a massive release of glutamate into

the space around the neuron. This results in

rapid death of these sensitized cells.

 

As we age, the blood supply to the brain is frequently impaired, either

because of atherosclerosis or

repeated syncopal episodes, leading to short periods of hypoxia.

Hypoglycemia produces lesions very similar to hypoxia and via the same

glutamate excitotoxic mechanism.

 

In fact, recent studies of diabetics

suffering from repeated episodes of hypoglycemia associated with over

medication with insulin, demonstrate brain atrophy and dementia.

 

Another cause of isolated cerebral hypoglycemia is impaired

transport of glucose into the brain across the blood-brain barrier. It

is known that glucose enters the brain by way of a glucose transporter,

and that in several conditions this transporter is impaired.

 

This includes aging, arteriosclerosis, and Alzheimer's disease.

 

This is especially important in the diabetic since prolonged elevation

of the blood sugar produces a down-regulation of the glucose transporter

and a

concomitant " brain hypoglycemia " that is exacerbated by repeated spells

of peripheral hypoglycemia common to type I diabetics.

 

With aging, one sees several of these energy deficiency syndromes,

such as mitochondrial injury, impaired cerebral blood flow, enzyme

dysfunction, and impaired glucose transportation, develop simutaneously.

 

 

 

This greatly magnifies excitotoxicity, leading to accelerated free

radical injury and a progressively rapid loss of cerebral function and

profound changes in cellular energy production.

 

It is suspected that at least in some of the neurodegenerative

diseases, Alzheimer's dementia and Parkinson's disease in particular,

this series of events plays a

major pathogenic role.

 

Chronic free radical accumulation would also result in an impaired

functional reserve of antioxidant

vitamins/minerals, antioxidant enzymes (SOD, catalase, and glutathione

peroxidase), and thiol compounds necessary for neural protection.

 

Chronic unrelieved stress, chronic infection, free radical generating

metals and toxins, and impaired DNA repair enzymes all add to this

damage.

 

It is estimated that the number of oxidative free radical injuries

to DNA number about 10,000 a day in humans.

 

Under conditions of cellular stress this may reach several hundred

thousand.Normally, these injuries are repaired by special DNA repair

enzymes. It is known that as we age these repair enzymes decrease or

become less efficient.

 

Also, some individuals are born with deficient repair enzymes from

birth as, for example, in the case of xeroderma pigmentosum. Recent

studies of Alzheimer's patients also demonstrate a significant

deficiency in DNA repair enzymes and high levels of lipid peroxidation

products in the affected parts of the brain.

 

It is also important to realize that the hippocampus of the brain,

most severely damaged in Alzheimer's dementia, is one of the most

vulnerable areas of the brain to low

glucose supply as well as low oxygen supply.

 

That also makes it very susceptible to glutamate/ free radical

toxicity.

 

Another interesting finding is that when cells are exposed to

glutamate they develop certain inclusions ( cellular debris) that not

only resembles the characteristic neurofibrillary tangles of Alzheimer's

dementia, but are immunologically identical as well.

 

Similarly, when experimental animals are exposed to the chemical

MPTP, they not only

develop Parkinson's disorder, but the older animals develop the same

inclusions ( Lewy bodies) as see in human Parkinson's.

 

There is growing evidence that protracted glutamate toxicity leads to

a condition of receptor loss characteristic of neurodegeneration.

 

This receptor loss produces a state of disinhibition that magnifies

excitotoxicity

during the later stage of the neurodegenerative process.

 

Special Functions of Ascorbic Acid

 

The brain contains one of the highest concentrations of ascorbic

acid in the body. Most are aware of ascorbic acid's function in

connective tissue synthesis and as a free radical scavenger. But,

ascorbic acid has other functions that make it rather unique.

 

In man, we know that certain areas of the brain have very high

concentrations of ascorbic acid, such as the nucleus accumbens and

hippocampus. The lowest levels are seen in the substantia nigra.

 

 

These levels seem to fluctuate with the electrical activity of the

brain. Amphetamine acts to increase ascorbic acid concentration in the

corpus striatum ( basal ganglion area) and decrease it in the

hippocampus, the memory imprint area of the brain. Ascorbic acid is

known to play a vital role in dopamine production as well.

 

One of the more interesting links has been between the secretion

of the glutamate neurotransmitter by the brain and the release of

ascorbic acid into the extracellular space.

 

This release of ascorbate can also be induced by systemic

administration of glutamate or aspartate, as would be seen in diets high

in these excitotoxins . The other neurotransmitters do not have a

similar effect on ascorbic acid release. This effect appears to be an

exchange mechanism.

 

That is, the ascorbic acid and glutamate exchange places.

 

Theoretically, high concentration of ascorbic acid in the diet could

inhibit glutamate

release, lessening the risk of excitotoxic damage. Of equal importance

is the free radical neutralizing effect of ascorbic acid.

 

There is now substantial evidence that ascorbic acid modulates the

electrophysiological as well as behavioral functioning of the brain.

 

 

It also attenuates the behavioral response of rats exposed to

amphetamine, which is known to act through an excitatory mechanism.

 

In part, this is due to the observed binding of ascorbic acid to the

glutamate receptor. This could mean that ascorbic acid holds great

potential in treating disease related to excitotoxic damage. Thus far,

there are no studies relating ascorbate metabolism in neurodegenerative

diseases.

There is at least one report of ascorbic acid deficiency in guinea pigs

producing histopathological changes similar to ALS.

 

It is known that as we age there is a decline in brain levels of

ascorbate. When accompanied by a similar decrease in glutathione

peroxidase, we see an accumulation of h302 and hence, elevated levels of

free radicals and lipid peroxidation. In one study, it was found that

with age not only does the extracellular concentration of ascorbic acid

decrease but the capacity of the brain ascorbic acid system to respond

to oxidative stress is impaired as well.

 

In terms of its antioxidant activity, vitamin C and E interact in

such a way as to restore each others active antioxidant state.

 

Vitamin C scavenges oxygen radicals in the aqueous phase and vitamin E

in the lipid, chain breaking, phase. The addition of vitamin C

suppresses the oxidative consumption of vitamin E almost totally,

probably because in the living organism the vitamin C in the aqueous

phase is adjacent to the lipid membrane layer containing the vitamin E.

 

When combined, the vitamin C is consumed faster during oxidative

stress than vitamin E. Once the vitamin C is totally consumed, vitamin E

begins to be depleted at an accelerated rate. N-acetyl-L-cysteine and

glutathione can reduce vitamin E consumption as well, but less

effectively than vitamin C. The real danger is when vitamin C is

combined with iron.

 

This is because the free iron oxidizes the ascorbate

to produce the free radical dehydroxyascorbate.

 

Alpha-lipoic acid acts powerfully to keep the ascorbate and tocopherol

in the reduced state

(antioxidant state).

 

As we age, we produce less of the transferrin

transport protein that normally binds free iron. As a result, older

individuals have higher levels of free iron within their tissues,

including brain, and are therefore at greater risk of widespread free

radical injury.

 

Neurodevelopment:

Recent studies have shown that glutamate plays a vital role in the

development of the nervous system, especially as regards neuronal

survival, growth and differentiation, development of circuits and

cytoarchitecture.

 

For example, it is known that deficiencies of glutamate in the brain

during neurogenesis can result in maldevelopment

of the visual cortices and may play a role in the development of

schizophrenia.

 

Likewise, excess glutamate can cause neural pathways

to produce improper connections, a process I call " miswiring of the

brain " .

 

Excess glutamate during embryogenesis has been shown to reduce

dendritic length and suppress axonal outgrowth in hippocampal neurons.

 

It is interesting to note that glutamate can produce classic toxicity in

the immature brain even before the glutamate receptors develop.

 

High glutamate levels can also affect astroglial proliferation as well

as

neuronal differentiation. It appears to act via the phosphoinositide

protein kinase C pathway.

 

It has been shown that during brain development there is an

overgrowth of neuronal connections and cellularity, and that at this

stage there is a peak in brain glutamate levels whose function it is to

remove excess connections and neuronal overexpression. This has been

referred to as " pruning " .

 

Importantly, glutamate excess during

synaptogenesis and pathway development has been shown to cause abnormal

connections in the hypothalamus that can lead to later

endocrinopathies.

 

In general, toxicological injury in the developing fetus carries

the greatest risk during the first two trimesters. But, this is not so

for the brain, which undergoes a spurt of growth that begins during the

third trimester and continues at least two years after birth.

 

Dendritic growth is maximal in the late fetal period to one year of age,

but may continue at a slower pace for several more years.

Neurotransmitter development also begins during the late fetal period

but continues for as long as four years after birth. This means that

alterations in dietary glutamate and aspartate are especially dangerous

to the fetus during pregnancy and for several years after birth.

 

The developing brain's succeptability to excitotoxicity varies , since

each brain

region has a distinct developmental profile. The type of excitotoxin

also appears to matter. For example, kianate is non-toxic to the

immature brain but extremely toxic to the mature brain. The glutamate

agonist, NMDA, is especially toxic up to postnatal day seven while

quisqualate and AMPA have peak toxicity from postnatal day seven through

fourteen.

 

L-cysteine is a powerful excitotoxin on the immature brain.

 

Myelination can also be affected by neurotoxins. In general,

excitotoxic substances affect dendrites and neurons more than axons but

axon demyelination has been demonstrated. During the myelination

process, each fiber tract has its own spatiotemporal pattern of

development, accompanied by significant biochemical changes, especially

in lipid metabolism.

 

More recent studies have shown an even more complicated pattern of CNS

myelination than previously thought. This is

of importance especially as regards the widespread use of aspartame,

because of this triple toxin's effects on neuronal proteins and DNA. Of

special concern is aspartame's methanol component and its breakdown

product, formaldehyde.

 

 

Also, it is known that the aspartate moiety undergoes spontanous

racemization in hot liquids to form D-aspartate, which has been

associated with tau proteins in Alzheimer's disease.

 

 

As you can see, the development of the brain is a very complex

process that occurs in a spatial and temporal sequence that is carefully

controlled by biochemical, structural, as well as neurophysiological

events.

 

Even subtle changes in these parameters can produce ultimate

changes in brain function that may vary from subtle alteration in

behavior and learning to autism, attention deficit disorder and violence

dyscontrol.

 

Experiments in which infant animals were exposed to MSG, have

demonstrated significant neurobehavioral deficits.87-88 Other studies

have shown that when pregnant female animals were fed MSG their

offspring demonstrated normal simple learning but showed significant

deficits in complex learning, accompanied by profound reductions in

several forebrain neurotransmitters.

 

In human this would mean that during infancy and early adolescence

learning would appear normal, but with entry into a more advance

education level, learning would be significantly impaired.

 

In several ways, this animal model resembles ADD and ADHD in humans.

Kubo and co-workers found that neonatal glutamate could severely injure

hippocampal CA1 neurons and dendrites and, as a result, impair

discriminative learning in rats.

 

It is also important to note that neonatal exposure to MSG has

been shown to cause significant alterations in neuroendocrine function

that can be prolonged.

 

By acting on the hypothalamus and its connections to the remainder of

the limbic connections, excitotoxins can profoundly affect behavior.

 

Conclusion

In this brief discussion of a most complicated and evolving

subject I have had to omit several important pieces of the puzzle. For

example, I have said little about the functional components of the

receptor systems, the glutamate transporter and its relation to ALS and

Alzheimer's dementia, receptor decay with aging and disease, membrane

effects of lipid peroxidation products, membrane fluidity, effects of

chronic inflammation on the glutamate/free radical cycle, stress

hormones and excitotoxicity, the role of insulin excess on the

eicosanoid system, or the detailed physiology of the glutamatergic

system.

 

I have also only briefly alluded to the toxicity of aspartame

and omitted its strong connection to brain tumor induction.

 

But, I have tried to show the reader that there is a strong

connection between dietary and indogenous excitotoxin excess and

neurological dysfunction and disease.

 

Many of the arguments by the food processing industry has been shown to

be false. For example, that

dietary glutamate does not enter the brain because of exclusion by the

blood-brain barrier, has been shown to be wrong, since glutamate can

enter by way of the unprotected areas of the brain such as the

circumventricular organs.

 

Also, as we have seen, chronic elevations of

blood glutamate can breech the intact blood-brain barrier.

 

In addition, there are numerous conditions under which the barrier is

made

incompetent.

 

As our knowledge of the pathophysiology and biochemistry of the

neurodegenerative diseases increases, the connection to excitotoxicity

has become stonger.

 

This is especially so with the interrelationship

between excitotoxicity and free radical generation and declining energy

production with aging.

 

Several factors of aging have been shown to

magnify this process. For example, as the brain ages its iron content

increases, making it more susceptible to free radical generation.

 

Also , aging changes in the blood brain barrier, micovascular changes

leading

to impaired blood flow, free radical mitochondrial injury to energy

generating enzymes, DNA adduct formation, alterations in glucose and

glutamate transporters and free radical and lipid peroxidation induced

alterations in the neuronal membranes all act to make the aging brain

increasingly susceptible to excitotoxic injury.

 

Over a lifetime of free radical injury due to chronic stress,

infections, trauma, impaired blood flow, hypoglycemia, hypoxia and poor

antioxidant defenses secondary to poor nutritional intake, the nervous

system is significantly weakened and made more susceptible to further

excitotoxic injury.

 

 

We known that a loss of neuronal energy generation

is one of the early changes seen with the neurodegenerative diseases.

This occurs long before clinical disease develops. But, even earlier is

a loss of neuronal glutathione functional levels.

 

I included the material about the special function of ascorbic

acid because few are aware of the importance of adequate ascorbate

levels for CNS function and neural protection against excitotoxicity. As

we have seen, it plays a vital role in neurobehavioral regulation and

the dopaminergic system as well,which may link ascorbate supplementation

to improvements in schizophrenia.

 

Our knowledge of this process opens up new avenues for treatment

as well as prevention of excitotoxic injury to the nervous system.

 

For example, there are many nutritional ways to improve CNS antioxidant

defenses and boost neuronal energy generation, as well as improve

membrane fluidity and receptor integrity. By using selective glutamate

blocking drugs or nutrients, one may be able to alter some of the more

devastating effects of Parkinson's disease. For example, there is

evidence that dopamine deficiency causes a disinhibition (overactivity)

of the subthalamic nucleus and that this may result in excitotoxic

injury to the substantia nigra.

 

By blocking the glutamatergic

neurons in this nucleus, one may be able to reduce this damage. There is

also evidence that several nutrients can significantly reduce

excitotoxicity.

 

For example, combinations of coenzyme Q10 and

niacinamide have been shown to protect against striatal excitotoxic

lesions. Methylcobolamine, phosphotidylserine, picnogenol and

acetyl-L-carnitine all protect against excitotoxicity as well.

 

Of particular concern is the toxic effects of these excitotoxic

compounds on the developing brain. It is well recognized that the

immature brain is four times more sensitive to the toxic effects of the

excitatory amino acids as is the mature brain.

 

This means that excitotoxic injury is of special concern from the fetal

stage to adolescence. There is evidence that the placenta concentrates

several of these toxic amino acids on the fetal side of the placenta.

 

Consumption

of aspartame and MSG containing products by pregnant women during this

critical period of brain formation is of special concern and should be

discouraged.

 

Many of the effects, such as endocrine dysfunction and

complex learning, are subtle and may not appear until the child is

older. Other hypothalamic syndromes associated with early excitotoxic

lesions include immune alterations and violence dyscontrol.

 

Over 100 million American now consume aspartame products and a

greater number consume products containing one or more excitotoxins.

There is sufficient medical literature documenting serious injury by

these additives in the concentrations presently in our food supply to

justify warning the public of these dangers.

 

The case against aspartame is especially strong.

 

JoAnn Guest

mrsj-

Dieta-

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