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.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 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.
In 1957, two ophthalmology 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 Ophthalmology 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 endogenous. 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.
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.
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 H2O2 as a by-product. (This is important
in stress, which has been shown to significantly increase brain levels of free
radicals.)
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.
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.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.48 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.
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.51,52 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.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.56,57In 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
simultaneously. 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.
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 H202 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.
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 susceptibility 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
spontaneous 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.
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 endogenous 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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____________
Article courtesy of Dr. Russell Blaylock and The
Medical Sentinel Journal
Authorized for replication as necessary to spread the
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