by Russell L. Blaylock, M.D.

   There are a growing number of clinicians and basic scientists who are
convinced that excitotoxins play a critical role in the development of
several neurological disorders, including migraines, seizures,
infections, abnormal neural development, certain endocrine disorders,
specific types of obesity, and especially the neurodegenerative
diseases; a group of diseases which includes: ALS, Parkinson’s disease,
Alzheimer’s disease, Huntington’s disease, and olivopontocerebellar
degeneration.

   An enormous amount of both clinical and experimental evidence has
accumulated over the past decade supporting this basic premise. Yet, the
FDA still refuses to recognize the immediate and long 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.

   The public must be made aware that 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 ( below toxic
levels) of excitotoxins are given to animals, they experience full
toxicity. 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 amino
acids, that react with specialized receptors in the brain in such a way
as to lead to destruction of certain types of brain cells. 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, is used by the brain only in very ,
very small concentrations - no more than 8 to 12ug. 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 cell death.

   The brain has several elaborate mechanisms to prevent accumulation of
MSG in the brain. First is the blood-brain barrier, a system that
impedes glutamate entry into the area of the brain cells. But, this
system was intended to protect the brain against occasional elevation of
glutamate of a moderate degree, as would be found with un-processed food
consumption. It was not designed to eliminate very high concentrations
of glutamate and aspartate consumed daily, several times a day, as we
see in modern society. Several experiments have demonstrated that under
such conditions, glutamate can by-pass this barrier system and enter the
brain in toxic concentrations. In fact, there is some evidence that it
may actually be concentrated within the brain with prolonged exposures.

   There are also several conditions under which the blood-brain barrier
( BBB) is made incompetent. Before birth, the BBB is incompetent and
will allow glutamate to enter the brain. It may be that for a
considerable period after birth the barrier may also incompletely
developed as well. Hypertension, diabetes, head trauma, brain tumors,
strokes, certain drugs, Alzheimer’s disease, vitamin and mineral
deficiencies, severe hypoglycemia, heat stroke, electromagnetic
radiation, ionizing radiation, multiple sclerosis, and certain
infections can all cause the barrier to fail. In fact, as we age the
barrier system becomes more porous, allowing excitotoxins in the blood
to enter the brain. So there are numerous instances under which
excitotoxin food additives can enter and damage the brain. Finally,
recent experiments have shown that glutamate and aspartate
( as in aspartame) can open the barrier itself.

  Another system used to protect the brain against environmental
excitotoxins, is a system within the brain that binds the glutamate
molecule  ( called the glutamate transporter) and transports  it to a
special storage cell ( the astrocyte) within a fraction of a second
after it is used as a neurotransmitter. This system can be overwhelmed
by high intakes of MSG, aspartame and other food excitotoxins. It is
also known that excitotoxins themselves can cause the generation of
numerous amounts of free radicals and that during the process of lipid
peroxidation ( oxidation of membrane fats) a substance is produced
called 4-hydroxynonenal. This chemical inhibits the glutamate
transporter, thus allowing glutamate to accumulate in the brain.

   Excitotoxins destroy neurons partly by stimulating the generation of
large numbers of free radicals. Recently, it has been shown that this
occurs not only within the brain, but also within other tissues and
organs as well ( liver and red blood cells). This could, from all
available evidence, increase all sorts of degenerative diseases such as
arthritis, coronary heart disease, and atherosclerosis,as well as induce
cancer formation. Certainly, we would not want to do something that
would significantly increase free radical production in the body. It is
known that all of the neurodegenerative disease, such as Parkinson’s
disease, Alzheimer’s disease, and ALS,  are associated with free radical
injury of the nervous system.

   It should also be appreciated that the effects of excitotoxin food
additives generally is 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 MSG and aspartame are probably not
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 effects. 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.

   In July, 1995 the Federation of American Societies for Experimental
Biology ( FASEB) conducted a definitive study for the FDA on the
question of safety of MSG. The FDA wrote a very deceptive 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. 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. In other words it has not been looked at. 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 a
hydrolyzed vegetable protein, vegetable protein, hydrolyzed plant
protein, caseinate, yeast extract, and natural flavoring. We know
experimentally, as stated, when these excitotoxin taste enhancers are
added together they become much more toxic. 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 of diet food, that contain two,
three or even four types of excitotoxins. We also know that excitotoxins
in a liquid form 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
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.

   In the case of ALS, amyotrophic lateral sclerosis, we know that
consumption of red meats and especially MSG itself, can significantly
elevate blood glutamate, much higher than is seen in the normal
population. Similar studies, as far as I am aware, have not been
conducted in patients with Alzheimer’s disease or Parkinson’s disease.
But, as a general rule I would certainly suggest that person’s with
either of these diseases avoid MSG containing foods as well as red
meats, cheeses, and pureed tomatoes, all of which are known to have high
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, based on present knowledge,
is in the case of ALS. Also, in the case of tomatoes, the plant contains
several powerful antioxidants known to block glutamate toxicity.

   Hydrolyzed vegetable protein should not be confused with hydrolyzed
vegetable oil. The oil does not contain appreciable concentration of
glutamate, it is an oil. Hydrolyzed vegetable protein is made by a
chemical process that breaks down the vegetable’s protein structure to
purposefully free the glutamate, as well as aspartate, another
excitotoxin. This brown powdery substance is used to enhance the flavor
of foods, especially meat dishes, soups, and sauces. Despite the fact
that some health food manufacturers have attempted to sell the idea that
this flavor enhancer is “ all natural” and “safe” because it is made
from vegetables, it is not. It is the same substance added to processed
foods. Experimentally, one can produce the same brain lesions using
hydrolyzed vegetable protein as by using MSG or aspartate.

   A growing list of excitotoxins is being discovered, including several
that are found naturally. For example, L- cysteine is a very powerful
excitotoxin. Recently, it has been added to certain bread dough and is
sold in health food stores as a supplement. Homocysteine, a metabolic
derivative, is also an excitotoxin. Interestingly, elevated blood levels
of homocysteine has recently been shown to be a major, if not the major,
indicator of cardiovascular disease and stroke. Equally interesting, is
the finding that elevated levels have also been implicated in
neurodevelopmental disorders, especially anencephaly and spinal
dysraphism ( neural tube defects). It is thought that this is the
protective mechanism of action 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.

    Recent studies have shown that persons affected by Alzheimer’s
disease also have widespread destruction of their retinal ganglion
cells. Interestingly, this is the area found to be affected when Lucas
and Newhouse first discovered the excitotoxicity of MSG. While this does
not prove that dietary glutamate and other excitotoxins cause or
aggravate Alzheimer’s disease, it makes one very suspicious. One could
argue a common intrinsic etiology for central nervous system neuronal
damage and retinal ganglion cell damage, but these findings are
disconcerting enough to warrant further investigations.

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 enzymes. For
example, the brains of Alzheimer’s disease patients have been found to
contain high concentration of lipolytic enzymes, which seems to indicate
accelerated membrane lipid peroxidation, again caused by free radical
generation.

   In the case of Parkinson’s disease, we know that one of the early
changes is the loss of glutathione from the neurons of the striate
system, especially in a nucleus called the substantia nigra. It is this
nucleus that is primarily affected in this disorder. Accompanying this,
is an accumulation of free iron, which is one of the most powerful free
radical generators known. One of the highest concentrations of iron in
the body is within the globus pallidus and the substantia nigra. The
neurons within the latter are especially vulnerable to oxidant stress
because the oxidant 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.
 

   Using a laser microprobe mass analyzer, researchers have recently
discovered that iron accumulation in Parkinson’s disease is primarily
localized in the neuromelanin granules ( which gives the nucleus its
black color). It has also been shown that there is dramatic accumulation
of aluminum within these granules. Most likely, the aluminum displaces
the bound iron, releasing highly reactive free iron. It is known that
even low concentrations of aluminum salts can enhance iron-induced lipid
peroxidation by almost an order of magnitude. Further, direct infusion
of iron into the substantia nigra nucleus in rodents can induce a
Parkinsonian syndrome, and a dose related decline in dopamine. Recent
studies indicate that individuals having Parkinson’s disease also have
defective iron metabolism.

   Another early finding in Parkinson’s disease is the reduction in
complex I enzymes within the mitochondria of this nucleus. It is well
known that the complex I enzymes are particularly sensitive to free
radical injury. These enzymes are critical to the production of cellular
energy. When cellular energy is decreased, the toxic effect of
excitatory amino acids increases dramatically, by as much as 200 fold.
In fact, when energy production is very low, even normal concentrations
of extracellular glutamate and aspartate can kill neurons.

   One of the terribly debilitating effects of Parkinson’s disease is a
condition called “ freezing up”, a state where the muscle are literally
frozen in place. There is recent evidence that this effect is due to the
unopposed firing of a special nucleus in the brain ( the subthalamic
nucleus). Interestingly, this nucleus uses glutamate for its
transmitter. Neuroscientist are exploring the use of glutamate blocking
drugs to prevent this disorder.

   And finally, there is growing evidence that similar free radical
damage, most likely triggered by toxic concentrations of excitotoxins,
causes ALS. Several studies have demonstrated lipid peroxidation product
accumulation within the spinal cords of ALS victims. Iron accumulation
has also been seen in the spinal cords of ALS victims.

   Besides the well known reactive oxygen species, such as super oxide,
hydroxyl ion, hydrogen peroxide, and singlet oxygen, there exist a whole
spectrum of reactive nitrogen species derived from nitric oxide, the
most important of which is peroxynitrate. These free radicals can attack
proteins, membrane lipids and DNA, both nuclear and mitochondrial, which
makes these radicals very dangerous.

   It is now known that glutamate acts on its receptor via a nitric
oxide mechanism.Overstimulation of the glutamate receptor can result in
accumulation of reactive nitrogen species, resulting in the
concentration of several species of dangerous free radicals. There is
growing evidence that, at least in part, this is how excess glutamate
damages nerve cells. In a multitude of studies, a close link has been
demonstrated between excitotoxity and free radical generation. Others
have shown that certain free radical scavengers ( anti-oxidants), have
successfully blocked excitotoxic destruction of neurons. For example,
vitamin E is known to completely block glutamate toxicity in vitro ( in
culture). Whether it will be as efficient in vivo  ( in a living animal)
is not known.  But, it is interesting in light of the recent
observations that vitamin E slows the course of Alzheimer’s disease, as
had already been demonstrated in the case of Parkinson’s disease. 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 anti-oxidants 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.

   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.) 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 exposure to free iron. 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 nucleus of Parkinsonian brains.

   When free radicals are generated, the first site of damage is to the
cell membranes, since they are composed of polyunsaturated fatty acid
molecules known to be highly susceptible to such attack. The process of
membrane lipid oxidation is known as lipid peroxidation and is usually
initiated by the hydroxal radical. We know that one’s diet can
significantly alter this susceptibility. For example, diets high in
omega 3-polyunsaturated fatty acids ( fish oils and flax seed oils) can
increase the risk of lipid peroxidation experimentally. Contrawise,
diets high in olive oil, a monounsaturtated oil, significantly lowers
lipid peroxidation risk. From the available research.The beneficial
effects of omega 3-fatty acid oils in the case of strokes and heart
attacks probably arises from the anticoagulant effect of these oils and
possibly the inhibition of release of arachidonic acid from the cell
membrane. But, olive oil has the same antithrombosis effect and
anticancer effect but also significantly lowers lipid peroxidation.

The Blood-Brain Barrier

   One of the MSG industry’s chief arguments for the safety of their
product is that glutamate in the blood cannot enter the brain because of
the blood-brain barrier ( BBB), a system of specialized capillary
structures designed to exclude toxic substance from entering the brain.
There are several criticisms of their defense. For example, it is known
that the brain, even in the adult, has several areas that normally do
not have a barrier system, called the circumventricular organs. These
include the hypothalamus, the subfornical organ, organium vasculosum,
area postrema, pineal gland, and the subcommisural organ. Of these, the
most important is the hypothalamus, since it is the controlling center
for all neuroendocrine regulation, sleep wake cycles, emotional control,
caloric intake regulation, immune system regulation and regulation of
the autonomic nervous system.  Interestingly, it has recently been found
that 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 can
easily increase hypothalamic levels as well. One of the earliest and
most consistent findings with exposure to MSG is damage to an area 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 circumventricular
organs.

   Another interesting observation is that chronic elevations of blood
glutamate can even seep through the normal blood-brain barrier when
these high concentrations are maintained over a long period of time.
This, naturally, would be the situation seen when individuals consume,
on a daily basis, foods high in the excitotoxins - MSG, aspartame and
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 daily 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. But, not only is the adjacent brain vulnerable, but the
openings act as a points of entry, eventually exposing the entire brain
to potentially toxic levels of glutamate. Several clinicians have
remarked on seeing MS patients who were made worse following exposure to
dietary excitotoxins. I have seen this myself.

   It is logical to assume that patients with the other
neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s
disease, and ALS will be made worse on diets high in excitotoxins.
Barrier disruption has been demonstrated in the case of Alzheimer’s
disease.

   Recently, it has been shown that not only can free radicals open the
blood-brain barrier, but excitotoxins can as well. In fact, glutamate
receptors have been demonstrated on the barrier itself. In a carefully
designed experiment, researchers produced opening of the blood-brain
barrier using injected iron as a free radical generator. When a powerful
free radical scavenger ( U-74006F) was used in this model, opening of
the barrier was significantly blocked. But, the glutamate blocker MK-801
acted even more effectively to protect the barrier.  The authors of this
study concluded that glutamate appears to be an important regulator of
brain capillary transport and stability, and that overstimulation of
NMDA ( glutamate) receptors on the blood-brain barrier appears to play
an important role in breakdown of the barrier system. What this also
means is that high levels of dietary glutamate or aspartate may very
well disrupt the normal blood-brain barrier, thus allowing more
glutamate to enter the brain, sort of a vicious cycle.

Relation to Cellular Energy Production

   Excitotoxin damage is heavily dependent on the energy state of the
cell. Cells with a normal energy generation systems that are efficiently
producing adequate amounts of cellular energy, 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. In fact,
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. 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 from
the mitochondria of the substantia nigra. ( Part of the Electron
Transport System.) 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 ( Those
involved in Parkinson’s and Huntington’s diseases.) are exposed to
microinjected excitotoxins there is a dramatic, and rapid fall in energy
production by these neurons. CoEnzyme Q10 has been shown, in this model,
to restore energy production but not to prevent cellular death. But when
combined with niacinamide, both cellular energy production and neuron
protection is seen. I would recommend for those with neurodegenerative
disorders, a combination of CoQ10, acetyl-L carnitine, niacinamide,
riboflavin, methylcobalamin, and thiamine.

   One of the newer revelation of modern molecular biology, is the
discovery of mitochondrial diseases, of which cellular energy deficiency
is a hallmark. In many of these disorders, significant clinical
improvement has been seen following a similar regimen of vitamins
combined with CoQ10 and L-carnitine. Acetyl L-carnitine enters the brain
in higher concentrations and also increases brain acetylcholine,
necessary for normal memory function. While these particular substances
have been found to significantly boost brain energy function they are
not alone in this important property. Phosphotidyl serine, Ginkgo
Biloba, vitamin B12, folate, magnesium, Vitamin K and several others are
also being shown to be important.

   While mitochrondial dysfunction is important in explaining why some
are more vulnerable to excitotoxin damage than others, it does not
explain injury in those with normal cellular metabolism. There are
several conditions under which energy metabolism is impaired. For
example, approximately one third of Americans suffer from what is known
as reactive hypoglycemia. That is, they respond to a meal composed of
either simple sugars or carbohydrates that are quickly broken down into
simple sugars ( 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 burn other substrates such as fats. There is
some evidence that several of the neurodegenerative diseases are related
to either excessive insulin release, as with Alzheimer’s disease, or
impaired glucose utilization, as we have seen in the case of Parkinson’s
disease and Huntington’s disease.

   It is my firm belief, based on clinical experience and physiological
principles, that many of these diseases occur primarily in the face of
either reactive hypoglycemia or “ brain hypoglycemia”. In at least two
well conducted studies it was found that pure Alzheimer’s dementia was
rare in those with normal blood sugar profiles, and that in most cases
Alzheimer’s patients had low blood sugars, and high CSF ( cerebrospinal
fluid) insulin levels. In my own limited experience with Parkinson’s and
ALS patients I have found a disproportionately high number suffering
from reactive hypoglycemia.

   I found it interesting that several ALS patients have observed an
association between their symptoms and gluten. That is, when they adhere
to a gluten free diet they improve clinically. It may be that by
avoiding gluten containing products, such as bread, crackers, cereal,
pasta ,etc, they are also avoiding products that are high on the
glycemic index, i.e. that produce reactive hypoglycemia. Also, all of
these food items are high in free iron. Clinically, hypoglycemia will
worsen the symptoms of most neurological disorders. We know that severe
hypoglycemia can, in fact, mimic ALS both clinically and pathologically.
It is also known that many of the symptoms of Alzheimer’s disease
resemble hypoglycemia, as if the brain is hypoglycemic in isolation.

   In studies of animals exposed to repeated mild episodes of hypoxia (
lack of brain oxygenation), it was found that such accumulated injuries
can trigger biochemical changes that resemble those seen in Alzheimer’s
patients. One of the effects of hypoxia is a massive release of
glutamate into the space around the neuron. This results in rapid death
of these sensitized cells. As we age, the blood supply to the brain is
frequently impaired, either because of atherosclerosis or repeated
syncopal episodes, leading to short periods of hypoxia. Hypoglycemia
produces lesions very similar to hypoxia and via the same glutamate
excitotoxic mechanism. In fact, recent studies of diabetics suffering
from repeated episodes of hypoglycemia associated with over medication
with insulin, demonstrate brain atrophy and dementia.

   Again, it should be realized that excessive glutamate stimulation
triggers a chain of events that in turn triggers the generation of large
numbers of free radical species, both as nitrogen species and oxygen
species. Once this occurs, especially with the accumulation of the
hydroxyl ion, destruction of the lipid components of the membranes
occurs, as lipid peroxidation. In addition, these free radicals damage
proteins and DNA as well. The most immediate DNA damage is to the
mitochondrial DNA, which controls protein expression within that
particular cell and its progeny. It is suspected that at least some of
the neurodegenerative diseases, Parkinson’s disease in particular, are
inherited in this way. But more importantly, it may be that accumulated
damage to the mitochondrial DNA secondary to progressive free radical
attack ( somatic mitochondrial injury) is the cause of most of the
neurodegenerative diseases that are not inherited. This would result
from an impaired reserve of antioxidant vitamins/minerals and enzymes,
increased cellular stress, chronic infection, free radical generating
metals and toxins, and impaired DNA repair enzymes.

   It is estimated that the number of oxidative free radical injuries to
DNA number about 10,000 a day in humans. Normally, these injuries are
repaired by special repair enzymes. It is known that as we age these
repair enzymes decrease or become less efficient. Also, some individuals
are born with deficient repair enzymes from birth as, for example, in
the case of xeroderma pigmentosum. Recent studies of Alzheimer’s
patients also demonstrate a significant deficiency in DNA repair enzymes
and high levels of lipid peroxidation products in the affected parts of
the brain. It is also important to realize that the hippocampus of the
brain, most severely damaged in Alzheimer’s dementia, is one of the most
vulnerable areas of the brain to low glucose supply as well as low
oxygen supply. That also makes it very susceptible to glutamate
toxicity.

   Another interesting finding is that when cells are exposed to
glutamate they develop certain inclusions ( cellular debris) that not
only resembles the characteristic neurofibrillary tangles of Alzheimer’s
dementia, but are immunologically identical as well. Similarly, when
experimental animals are exposed to the chemical MPTP, they not only
develop Parkinson’s disorder, but the older animals develop the same
inclusions ( Lewy bodies) as see in human Parkinson’s.

Eicosanoids and Excitotoxins

   It is known that one of the destructive effects triggered by
excitotoxins is the release of arachidonic acid from the cell membrane
and the initiation of the eicosanoid reactions. Remember, glutamate
primarily acts by opening the calcium pore, allowing calcium to pour
into the cell’s interior. Intracellular calcium in high concentrations
initiates the enzymatic release of arachidonic acid from the cell
membrane, where it is then attacked by two enzymes systems, the
cyclooxygenase system and the lipooxgenase system. These in turn produce
a series of compounds that can damage cell membranes, proteins and DNA,
primarily by free radical production, but also directly by the "harmful
eicosanoids."

   Biochemically, we know that high glycemic carbohydrate diets, known
to stimulate the excess release of insulin, can trigger the production
of "harmful eicosanoids." We should also recognize that simple sugars
are not the only substances that can trigger the release of insulin. One
of the more powerful triggers includes certain amino acids, including
leucine, alanine, and taurine. Glutamine, while not acting as an insulin
trigger itself, markedly potentiates insulin release by leucine. This is
why, except under certain situations, individual "free" amino acids
should be avoided.

   It is known that excitotoxins can also stimulate the release of these
"harmful eicosanoids." So that in the situation of a hypoglycemic
individual, they would be subjected to production of harmful eicosanoids
directly by the high insulin levels, as well as by elevated glutamate
levels. Importantly, both of these events significantly increase free
radical production and hence, lipid peroxidation of cellular membranes.
It should be remembered that diets high in arachidonic acid, such as egg
yellows, organs meats, and liver, may be harmful to those subjected to
excessive excitotoxin exposure.

   And finally, in one carefully conducted experiment, it was shown that
insulin significantly increases glutamate toxicity in cortical cell
cultures and that this magnifying effect was not due to insulin’s effect
on glucose metabolism. That is, the effect was directly related to
insulin interaction with cell membranes. Interestingly, insulin
increased toxic sensitivity to other excitotoxins as well.

The Special Role of Flavanoids

   Flavonoids are diphenylpropanoids found in all plant foods. They are
known to be strong antioxidants and free radical scavengers. There are
three major flavonols - quercetin, Kaempferol, and myricetin, and two
major flavones - luteolin and apigenin. Seventy percent of the flavonoid
intake in the average diet consist of quercetin, the main source of
which is tea ( 49%), onions ( 29%), and apples ( 7%). Fortunately,
flavonoids are heat stable, that is, they are not destroyed during
cooking. Other important flavonoids include catechin,
leucoanthocyanidins,  anthocyanins, hesperedin and naringenin.

   Most interest in the flavonoids stemmed from their ability to inhibit
tumor initiation and growth. This was especially true of quercetin and
naringenin, but also seen with hesperetin and the isoflavone, genistein.
There appears to be a strong correlation between their anticarcinogenic
potential and their ability to squelch free radicals. But, in the case
of genistein and quercetin, it also has to do with their ability to
inhibit tyrosine kinase and phosphoinositide phosphorylase, both
necessary for mammary cancer and glioblastoma ( a highly malignant brain
tumor) growth and development.

   As we have seen, there is a close correlation between insulin,
excitotoxins, free radicals and eicosanoid production. Of particular
interest, is the finding that most of the flavonoids, especially
quercetin, are potent and selective inhibitors of delta-5-lipooxygenase
enzyme which initiates the production of eicosanods. Flavones are also
potent and selective inhibitors of the enzyme cyclooxygenase ( COX)
which is responsible for the production of thromboxane A2, one of the
"harmful eicosanoids". The COX-2 enzymes is associated only with
excitatory type neurons in the brain and appears to play a major role in
neurodegeneration.

   One of the critical steps in the production of eicosanoids is the
liberation of arachidonic acid from the cell membrane by phospholipase
A2. Flavonones such as naringenin ( from grapefruits) and hesperetin (
citrus fruits) produce a dose related inhibition of phospholipase A2 (
80% inhibition), thereby inhibiting the release of arachidonic acid. The
non-steroidal anti-inflammatory drugs act similarly to block the
production of inflammatory eicosanoids.

   What makes all of this especially interesting is that recently, two
major studies have found that not only can non-steroidal anti-
inflammatories slow the course of Alzheimer’s disease, but they may
prevent it as well. But, these drugs can have significant side effects,
such as GI bleeding, liver and kidney damage. In high doses, the
flavonoids have shown a similar ability to reduce "harmful eicosanoid"
production and should have the same beneficial effect on the
neurodegenerative diseases without the side effects. Also, these
compounds are powerful free radical scavengers and would be expected to
reduce excitotoxicity as well.

   But, there is another beneficial effect. There is experimental, as
well as clinical evidence, that the flavonoids can reduce capillary
leakage and strengthen the blood brain barrier. This has been shown to
be true for rutin, hesperedin and some chalcones. Rutin and hesperedin
have also been shown to strengthen capillary walls. In the form of
hesperetin methyl chalcone, the hesperedin molecule is readily soluble
in water, significantly increasing its absorbability. Black currents
have the highest concentration of hesperetin of any fresh fruit, and in
a puree form, is even more potent.

   The importance of these compounds again emphasizes the need for high
intakes of fruits and vegetables in the diet, and may explain the low
incidence of many of these disorders in strict vegetarians, since this
would supply a high concentration of flavonoids, carotenoids, vitamins,
minerals, and other antioxidants to the body. Normally, the flavonoids
from fruits and vegetables are only incompletely absorbed, so that
relatively high concentrations would be needed to attain the same
therapeutic levels seen in these experiments. Juice Plus allows us to
absorb high, therapeutic concentrations of these flavonoids by a process
called cryodehydration. This process removes the water and sugar from
fruits and vegetable but retains their flavonoids in a fully functional
state. Also the process allows one to consume large amounts of fruits
and vegetables that would be impossible with the whole plant.

Iron and Health

For decades we, especially women, have been told that we need extra iron
for health -that it builds healthy blood. But, recent evidence indicates
that iron and copper may be doing more harm than good in most cases. It
has been well demonstrated that iron and copper are two of the most
powerful generators of free radicals. This is because they catalyze the
conversion of hydrogen peroxide into the very powerful and destructive
hydroxyl radical. It is this radical that does so much damage to
membrane lipids and DNA bases within the cell. It also plays a major
role in the oxidation of LDL-cholesterol, leading to heart attacks and
strokes.

Males begin to accumulate iron shortly after puberty and by middle age
have 1000mg of stored iron in their bodies. Women, by contrast, because
of menstruation, have only 300 mg of stored iron. But, after menopause
they begin to rapidly accumulate iron so that by middle age they have
about 1500 mg of stored iron. It is also known that the brain begins to
accumulate iron with aging. Elevated iron levels are seen with all of
the neurodegenerative diseases, such as Alzheimer’s dementia,
Parkinson’s disease, and ALS. It is thought that this iron triggers free
radical production within the areas of the brain destroyed by these
diseases. For example, the part of the brain destroyed by Parkinson’s
disease, the substantia nigra, has very high levels of free iron.

Normally, the body goes to great trouble to make sure all iron and
copper in the body is combined to a special protein for transport and
storage. But, with several of these diseases, we see a loss of these
transport and storage proteins. This is where flavonoids come into play.
We know that many of the flavonoids ( especially quercitin, rutin,
hesperidin, and naringenin) are strong chelators of iron and copper. In
fact, drinking iced tea with a meal can reduce iron absorption by as
much as 87%. But, flavonoids in the diet will not make you iron
deficient.

Phosphotidyl serine and Excitotoxity

   Recent clinical studies indicate that phophotidyl serine can
significantly improve the mental functioning of a significant number of
Alzheimer’s patients, especially during the early stages of the disease.
We know that the brain normally contains a large concentration of
phosphotidyl serine. Interestingly, this compound has a chemical
structure similar to L-glutamate, the main excitatory neurotransmitter
in the brain. Binding studies show that phosphotidyl serine competes
with L-glutamate for the NMDA type glutamate receptor. What this means
is that phosphotidyl serine is a very effective protectant against
glutamate toxicity. Unfortunately, it is also very expensive.

The Many Functions of Ascorbic Acid

   The brain contains one of the highest concentrations of ascorbic acid
in the body. Most are aware of its function in connective tissue
synthesis and as a free radical scavenger. But, ascorbic acid has other
functions that make it rather unique. Ascorbic acid in solution is a
powerful reducing agent where it undergoes rapid oxidation to form
dehydroascorbic acid. Oxidation of this compound is accelerated by high
ph, temperature and some transitional metals, such as iron and copper.
The oxidized form of ascorbic acid can promote lipid peroxidation and
protein damage. This is why it is vital that you take antioxidants
together, since several, such as vitamin E ( as D- alpha-tocopherol) and
alpha-lipoic acid,  act to regenerate the reduced form of the vitamin.

   In man, we know that certain areas of the brain have very high
concentrations of ascorbic acid, such as the nucleus accumbens and
hippocampus. The lowest levels are seen in the substantia nigra. These
levels seem to fluctuate with the electrical activity of the brain.
Amphetamine acts to increase ascorbic acid concentration in the corpus
striatum ( basal ganglion area) and decrease it in the hippocampus, the
memory imprint area of the brain. Ascorbic acid is known to play a vital
role in dopamine production as well.

   One of the more interesting links has been between the secretion of
the glutamate neurotransmitter by the brain and the release of ascorbic
acid into the extracellular space. This release of ascorbate can also be
induced by systemic administration of glutamate or aspartate, as would
be seen in diets high in these excitotoxins . The other
neurotransmitters do not have a similar effect on ascorbic acid release.
This effect appears to be an exchange mechanism. That is, the ascorbic
acid and glutamate exchange places. Theoretically, high concentration of
ascorbic acid in the diet could inhibit glutamate release, lessening the
risk of excitotoxic damage. Of equal importance is the free radical
neutralizing effect of ascorbic acid.

   There is now substantial evidence that ascorbic acid modulates the
electrophysiological as well as behavioral functioning of the brain. It
also attenuates the behavioral response of rats exposed to amphetamine,
which is known to act through an excitatory mechanism. In part, this is
due to the observed binding of ascorbic acid to the glutamate receptor.
This could mean that ascorbic acid holds great potential in treating
disease related to excitotoxic damage. Thus far, there are no studies
relating ascorbate metabolism in neurodegenerative diseases. There is at
least one report of ascorbic acid deficiency in guineas pigs producing
histopathological changes similar to ALS.

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

   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 was consumed faster during oxidative
stress than the vitamin E. Once the vitamin C was totally consumed, the
vitamin E began 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. Recent experiments have shown that such combinations
can produce widespread destruction within the striate areas of the
brain. This is because the free iron oxidizes the ascorbate to produce
the powerful free radical hydroxyascorbate. 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.

Conclusion

   In this discussion, I tried to highlight some of the more pertinent
of the recent findings related to excitotoxicity in general and
neurodegenerative diseases specifically. In no way is this an all
inclusive discussion of this topic. There are many areas I had to omit
because of space, such as alpha-lipoic acid, an antioxidant that holds
great promise in combatting many of these diseases. Also, I did not go
into detail concerning the metabolic stimulants, the relationship
between exercise and degenerative nervous system diseases, the
protective effect of methycobalamin, and the various disorders related
to excitotoxins.

   I also purposely omitted discussions of magnesium to keep this paper
short. It is my experience, that magnesium is one of the most important
neuroprotectants known. I would encourage those who suffer from one of
the excitotoxin related disorders to avoid, as much as possible, food
borne excitotoxin additives and to utilize the substances discussed
above. The fields of excitotoxin research, in combination with research
on free radicals and eicosanoids, are growing very rapidly and new
information arises daily.  Great promise exist in the field of flavonoid
research as regards many of these neurodegenerative diseases as well as
in our efforts to prevent neurodegeneration itself.

   A recent study has demonstrated that aspartame feeding to animals
results in an accumulation of formaldehyde within the cells, with
evidence of significant damage to cellular proteins and DNA. In fact,
the formaldehyde accumulated with prolonged use of aspartame. With this
damning evidence, one would have to be suicidal to continue the use of
aspartame sweetened foods, drinks and medicines. The use of foods
containing excitotoxin additives is especially harmful to the unborn and
small children. By age 4 the brain is only 80% formed. By age 8, 90% and
by age 16 it is fully formed, but still undergoing changes and rewiring
( plasticity). We know that the excitotoxins have a devastating effect
on formation of the brain ( wiring of the brain) and that such  exposure
can cause the brain to be "miswired." This may explain the significant,
almost explosive increase in ADD and ADHD. Glutamate feeding to pregnant
animals produces a syndrome almost identical to ADD. It has also been
shown that a single feeding of MSG after birth can increase free
radicals in the offspring’s brain that last until adolescence.
Experimentally, we known that infants are 4X more sensitive to the
toxicity of excitotoxins than are adults. And, of all the species
studied, cats, dogs, primates, chickens, guinea pigs, and rats, humans
are by far the most sensitive to glutamate toxicity. In fact, they are
5x more sensitive than rats and 20x more sensitive than non-human
primates.

   I have been impressed with the dramatic improvement in children with
ADD and ADHD following abstention from excitotoxin use. It requires care
monitoring of these children. Each time they are exposed to these
substances, they literally go bonkers. It is ludicrous, with all we know
about the destructive effects of excitotoxins, to continue to allow
ourselves and our children to continue on this destructive path.