Russell L. Blaylock, M.D.
http://www.royalrife.com/
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 tastes 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 allow our children and
ourselves to continue on this destructive path.
This article and more information can be found at
http://www.aspartamekills.com
No comments:
Post a Comment