Excitotoxins, Neurodegeneration and Neurodevelopment --- Aspartame & MSG

[Guest guest]

My comment - A sugar substitute, aspartame [ the technical name for the

brand names, NutraSweet, Equal, Spoonful, and Equal-Measure.], as well as

MSG are excitotoxins and are discussed in this article.

 

Excitotoxins, Neurodegeneration and Neurodevelopment

By Russell L. Blaylock, M.D

_http://www.dorway.com/blayenn.html_ (http://www.dorway.com/blayenn.html)

 

 

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.1

 

 

An enormous amount of both clinical and experimental evidence has

accumulated over the past decade supporting this basic premise.2 Yet, the FDA

still

refuses to recognize the immediate and long term danger 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

taste 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

certai

n 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.3 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.4 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.5 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.6

 

 

More recent molecular studies have disclosed the mechanism of this

destruction in some detail.7 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.8 The FDA wrote a very deceptive summery 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.9 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 links 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.10 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.11

 

 

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.<12 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.13

 

 

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.14

 

 

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.15 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).16 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.17

 

 

One interesting study found that persons affected by Alzheimer's disease

also have widespread destruction of their retinal ganglion cells.18

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.19 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. 20,21,22

 

 

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.23 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.24 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.25

 

 

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).26 It

has also been shown that there is dramatic accumulation of aluminum within

these granules.27 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.28

 

 

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

enzymes within the mitochondria of this nucleus.29 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.30 Several studies have demonstrated lipid

peroxidation product accumulation within the spinal cords of ALS victims as well

as iron accumulation.31

 

 

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

mechanism.32 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.33 In a multitude of studies, a close link has been demonstrated

between excitotoxicity and free radical generation.34-37

 

 

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.38 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.39 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 use 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.40

 

 

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.41 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.42

 

 

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.43 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 cr

iticisms 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.44 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

condition 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.45 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.46

 

 

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

blood-brain barrier, but excitotoxins can as well.47 In fact, glutamate

receptors have been demonstrated on the barrier itself.49 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.49 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.

 

 

It 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.50 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.51-52Interestingly, 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.53 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.54 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.55

 

 

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.55-57 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.58 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.59

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.60

 

 

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.61-62 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.63 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.64 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.65 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.66 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.67-68 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.69 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.70 There is growing evidence that protracted glutamate

toxicity leads to a condition of receptor loss characteristic of

neurodegeneration.71 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.72 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.73 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.74 It also

attenuates the behavioral response of rats exposed to amphetamine, which is

known to act through an excitatory mechanism.75 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 guineas pigs producing histopathological changes similar

to ALS.76

 

 

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.77

 

 

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.78 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.79 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.80

 

 

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.81 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.82-83

 

 

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.84, 85, 86

 

 

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.89-90

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.91

 

 

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.92-93 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.94 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.95 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.

 

 

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