-
-
- There are a growing number of clinicians and basic scientists
who are convinced that a group of compounds called excitotoxins play a
critical role in the development of several neurological disorders including
migraines, seizures, infections, abnormal neural development, certain endocrine
disorders, neuropsychiatric disorders, learning disorders in children,
AIDS dementia, episodic violence, lyme borreliosis, hepatic encephalopathy,
specific types of obesity, and especially the neurodegenerative diseases,
such as ALS, Parkinson's disease, Alzheimer's disease, Huntington's disease,
and olivopontocerebellar degeneration.1
-
- An enormous amount of both clinical and experimental
evidence has accumulated over the past decade supporting this basic premise.
2 Yet, the FDA still refuses to recognize the immediate and long term danger
to the public caused by the practice of allowing various excitotoxins to
be added to the food supply, such as MSG, hydrolyzed vegetable protein,
and aspartame. The amount of these neurotoxins added to our food has increased
enormously since their first introduction. For example, since 1948 the
amount of MSG added to foods has doubled every decade. By 1972 262,000
metric tons were being added to foods. Over 800 million pounds of aspartame
have been consumed in various products since it was first approved. Ironically,
these food additives have nothing to do with preserving food or protecting
its integrity. They are all used to alter the taste of food. MSG, hydrolyzed
vegetable protein, and natural flavoring are used to enhance the taste
of food so that it taste better. Aspartame is an artificial sweetener.
-
- These toxins ( excitotoxins) are not present in just
a few foods, but rather in almost all processed foods. In many cases they
are being added in disguised forms, such as natural flavoring, spices,
yeast extract, textured protein, soy protein extract, etc. Experimentally,
we know that when subtoxic levels of excitotoxins are given to animals
in divided doses, they experience full toxicity, i.e.they are synergistic.
Also, liquid forms of excitotoxins, as occurs in soups, gravies and diet
soft drinks are more toxic than that added to solid foods. This is because
they are more rapidly absorbed and reach higher blood levels.
-
- So, what is an excitotoxin? These are substances, usually
acidic amino acids, that react with specialized receptors in the brain
in such a way as to lead to destruction of certain types of neurons. Glutamate
is one of the more commonly known excitotoxins. MSG is the sodium salt
of glutamate. This amino acid is a normal neurotransmitter in the brain.
In fact, it is the most commonly used neurotransmitter by the brain. Defenders
of MSG and aspartame use, usually say: How could a substance that is used
normally by the brain cause harm? This is because, glutamate, as a neurotransmitter,
exists in the extracellular fluid only in very, very small concentrations
- no more than 8 to 12uM. When the concentration of this transmitter rises
above this level the neurons begin to fire abnormally. At higher concentrations,
the cells undergo a specialized process of delayed cell death known as
excitotoxicity, that is, they are excited to death.
-
- It should also be appreciated that the effects of excitotoxin
food additives generally are not dramatic. Some individuals may be especially
sensitive and develop severe symptoms and even sudden death from cardiac
irritability, but in most instances the effects are subtle and develop
over a long period of time. While the food additives, MSG and aspartame,
are probably not direct causes of the neurodegenerative diseases, such
as Alzheimer's dementia, Parkinson's disease, or amyotrophic lateral sclerosis,
they may well precipitate these disorders and certainly worsen their pathology
as we shall see. It may be that many people with a propensity for developing
one of these diseases would never develop a full blown disorder had it
not been for their exposure to high levels of food borne excitotoxin additives.
Some may have had a very mild form of the disease had it not been for the
exposure. Likewise, food borne excitotoxins may be harmful to those suffering
from strokes, head injury and HIV infection and certainly should not be
used in a hospital setting.
-
- How Excitotoxins Were Discovered
-
- In 1957, two opthalmology residents, Lucas and Newhouse,
were conducting an experiment on mice to study a particular eye disorder.3
During the course of this experiment they fed newborn mice MSG and discovered
that all demonstrated widespread destruction of the inner nerve layer of
the retina. Similar destruction was also seen in adult mice but not as
severe as the newborns. The results of their experiment was published in
the Archives of Opthalmology and soon forgotten. For ten years prior to
this report, large amounts of MSG were being added not only to adult foods
but also to baby foods in doses equal to those of the experimental animals.
-
- Then in 1969, Dr. John Olney, a neuroscientist and neuropathologist
working out of the Department of Psychiatry at Washington University in
St. Louis, repeated Lucas and Newhouse's experiment. 4 His lab assistant
noticed that the newborn of MSG exposed mice were grossly obese and short
in statue. Further examination also demonstrated hypoplastic organs, including
pituitary, thyroid, adrenal as well as reproductive dysfunction. Physiologically,
they demonstrated multiple endocrine deficiencies, including TSH, growth
hormone, LH, FSH, and ACTH. When Dr. Olney examined the animal's brain,
he discovered discrete lesions of the arcuate nucleus as well as less severe
destruction of other hypothalamic nuclei. Recent studies have shown that
glutamate is the most important neurotransmitter in the hypothalamus.5
Since this early observation, monosodium glutamate and other excitatory
substances have become the standard tool in studying the function of the
hypothalamus. Later studies indicated that the damage by monosodium glutamate
was much more widespread, including the hippocampus, circumventricular
organs, locus cereulus, amygdala- limbic system, subthalamus, and striatum.6
-
- More recent molecular studies have disclosed the mechanism
of this destruction in some detail.7 Early on it was observed that when
neurons in vitro were exposed to glutamate and then washed clean, the cells
appeared perfectly normal for approximately an hour, at which time they
rapidly underwent cell death. It was discovered that when calcium was removed
from the medium, the cells continued to survive. Subsequent studies have
shown that glutamate, and other excitatory amino acids, attach to a specialized
family of receptors ( NMDA, kainate, AMPA and metabotrophic) which in turn,
either directly or indirectly, opens the calcium channel on the neuron
cell membrane, allowing calcium to flood into the cell. If unchecked, this
calcium will trigger a cascade of reactions, including free radical generation,
eicosanoid production, and lipid peroxidation, which will destroy the cell.
With this calcium triggered stimulation, the neuron becomes very excited,
firing its impulses repetitively until the point of cell death, hence
the name excitotoxin. The activation of the calcium channel via the NMDA
type receptors also involves other membrane receptors such as the zinc,
magnesium, phencyclidine, and glycine receptors
-
- In many disorders connected to excitotoxicity, the source
of the glutamate and aspartate is indogenous. We know that when brain cells
are injured they release large amounts of glutamate from surrounding astrocytes,
and this glutamate can further damage surrounding normal neuronal cells.
This appears to be the case in strokes, seizures and brain trauma. But,
food born excitotoxins can add significantly to this accumulation of toxins.
-
- The FDA's Response
-
- In July, 1995 the Federation of American Societies for
Experimental Biology ( FASEB) conducted a definitive study for the FDA
on the question of safety of MSG.8 The FDA wrote a very deceptive summery
of the report in which they implied that, except possibly for asthma patients,
MSG was found to be safe by the FASEB reviewers. But, in fact, that is
not what the report said at all. I summarized, in detail, my criticism
of this widely reported FDA deception in the revised paperback edition
of my book, Excitotoxins: The Taste That Kills, by analyzing exactly what
the report said, and failed to say.9 For example, it never said that MSG
did not aggravate neurodegenerative diseases. What they said was, there
were no studies indicating such a link. Specifically, that no one has conducted
any studies, positive or negative, to see if there is a link. A vital difference.
-
- Unfortunately, for the consumer, the corporate food processors
not only continue to add MSG to our foods but they have gone to great links
to disguise these harmful additives. For example, they use such names as
hydrolyzed vegetable protein, vegetable protein, textured protein, hydrolyzed
plant protein, soy protein extract, caseinate, yeast extract, and natural
flavoring. We know experimentally that when these excitotoxin taste enhancers
are added together they become much more toxic than is seen individually.
10 In fact, excitotoxins in subtoxic concentrations can be fully toxic
to specialized brain cells when used in combination. Frequently, I see
processed foods on supermarket shelves, especially frozen or diet foods,
that contain two, three or even four types of excitotoxins. We also know,
as stated, that excitotoxins in liquid forms are much more toxic than
solid forms because they are rapidly absorbed and attain high concentration
in the blood. This means that many of the commercial soups, sauces, and
gravies containing MSG are very dangerous to nervous system health, and
should especially be avoided by those either having one of the above mentioned
disorders, or who are at a high risk of developing one of them. They should
also be avoided by cancer patients and those at high risk for cancer, because
of the associated generation of free radicals and lipid peroxidation.11
-
- In the case of ALS, amyotrophic lateral sclerosis, we
know that consumption of red meats and especially MSG itself, can significantly
elevate blood glutamate, much higher than is seen in the normal population.12
Similar studies, as far as I am aware, have not been conducted in patients
with Alzheimer's disease or Parkinson's disease. But, as a general rule
I would certainly suggest that person's with either of these diseases avoid
MSG containing foods as well as red meats, cheeses, and pureed tomatoes,
all of which are known to have higher levels of glutamate.
-
- It must be remembered that it is the glutamate molecule
that is toxic in MSG ( monosodium glutamate). Glutamate is a naturally
occurring amino acid found in varying concentrations in many foods. Defenders
of MSG safety allude to this fact in their defense. But, it is free glutamate
that is the culprit. Bound glutamate, found naturally in foods, is less
dangerous because it is slowly broken down and absorbed by the gut, so
that it can be utilized by the tissues, especially muscle, before toxic
concentrations can build up. Therefore, a whole tomato is safer than a
pureed tomato. The only exception to this as stated, based on present knowledge,
is in the case of ALS. Also, the tomato plant contains several powerful
antioxidants known to block glutamate toxicity.13
-
- Hydrolyzed vegetable protein is a common food additive
and may contain at least two excitotoxins, glutamate and cysteic acid.
Hydrolyzed vegetable protein is made by a chemical process that breaks
down the vegetable's protein structure to purposefully free the glutamate,
as well as aspartate, another excitotoxin. This brown powdery substance
is used to enhance the flavor of foods, especially meat dishes, soups,
and sauces. Despite the fact that some health food manufacturers have attempted
to sell the idea that this flavor enhancer is " all natural"
and "safe" because it is made from vegetables, it is not. It
is the same substance added to processed foods. Experimentally, one can
produce the same brain lesions using hydrolyzed vegetable protein as by
using MSG or aspartate.14
-
- A growing list of excitotoxins are being discovered,
including several that are found naturally. For example, L- cysteine is
a very powerful excitotoxin. Recently, it has been added to certain bread
dough and is sold in health food stores as a supplement. Homocysteine,
a metabolic derivative, is also an excitotoxin.15 Interestingly, elevated
blood levels of homocysteine has recently been shown to be a major, if
not the major, indicator of cardiovascular disease and stroke. Equally
interesting, is the finding that elevated levels have also been implicated
in neurodevelopmental disorders, especially anencephaly and spinal dysraphism
( neural tube defects).16 It is thought that this is the protective mechanism
of action associated with the use of the prenatal vitamins B12, B6, and
folate when used in combination. It remains to be seen if the toxic effect
is excitatory or by some other mechanism. If it is excitatory, then unborn
infants would be endangered as well by glutamate, aspartate ( part of the
aspartame molecule), and the other excitotoxins. Recently, several studies
have been done in which it was found that all Alzheimer's patients examined
had elevated levels of homocysteine.17
-
- One interesting study found that persons affected by
Alzheimer's disease also have widespread destruction of their retinal ganglion
cells.18 Interestingly, this is the area found to be affected when Lucas
and Newhouse first discovered the excitotoxicity of MSG. While this does
not prove that dietary glutamate and other excitotoxins cause or aggravate
Alzheimer's disease, it is powerful circumstantial evidence. When all of
the information known concerning excitatory food additives is analyzed,
it is hard to justify continued approval by the FDA for the widespread
use of these food additives.
-
- The Free Radical Connection
-
- It is interesting to note that many of the same neurological
diseases associated with excitotoxic injury are also associated with accumulations
of toxic free radicals and destructive lipid oxidation products.19 For
example, the brains of Alzheimer's disease patients have been found to
contain high concentration of lipid peroxidation products and evidence
of free radical accumulation and damage. 20,21,22
-
- In the case of Parkinson's disease, we know that one
of the early changes is the loss of one of the primary antioxidant defense
systems, glutathione, from the neurons of the striate system, and especially
in the substantia nigra.23 It is this nucleus that is primarily affected
in this disorder. Accompanying this, is an accumulation of free iron, which
is one of the most powerful free radical generators known.24 One of the
highest concentrations of iron in the body is within the globus pallidus
and the substantia nigra. The neurons within the latter are especially
vulnerable to oxidant stress because the catabolic metabolism of the transmitter-dopamine-
can proceed to the creation of very powerful free radicals.That is, it
can auto-oxidize to peroxide,which is normally detoxified by glutathione.
As we have seen, glutathione loss in the substantia nigra is one of the
earliest deficiencies seen in Parkinson's disease. In the presence of high
concentrations of free iron, the peroxide is converted into the dangerous,
and very powerful free radical, hydroxide. As the hydroxide radical diffuses
throughout the cell, destruction of the lipid components of the cell takes
place, a process called lipid peroxidation. Of equal importance is the
generation of the powerful peroxynitrite radical, which has been shown
to produce serious injury to cellular proteins and DNA, both mitochondrial
and nuclear.25
-
- Using a laser microprobe mass analyzer, researchers have
recently discovered that iron accumulation in Parkinson's disease is primarily
localized in the neuromelanin granules ( which gives the nucleus its black
color).26. It has also been shown that there is dramatic accumulation
of aluminum within these granules.27 Most likely, the aluminum displaces
the bound iron, releasing highly reactive free iron. It is known that even
low concentrations of aluminum salts can enhance iron-induced lipid peroxidation
by almost an order of magnitude. Further, direct infusion of iron into
the substantia nigra nucleus in rodents can induce a Parkinsonian syndrome,
and a dose related decline in dopamine. Recent studies indicate that individuals
having Parkinson's disease also have defective iron metabolism. 28
-
- Another early finding in Parkinson's disease is the reduction
in complex I enzymes within the mitochondria of this nucleus.29 It is well
known that the complex I enzymes are particularly sensitive to free radical
injury. These enzymes are critical to the production of cellular energy.
As we shall see, when cellular energy is decreased, the toxic effect of
excitatory amino acids increases dramatically.
-
- In the case of ALS there is growing evidence that similar
free radical damage, most likely triggered by toxic concentrations of excitotoxins,
plays a major role in the disorder.30. Several studies have demonstrated
lipid peroxidation product accumulation within the spinal cords of ALS
victims as well as iron accumulation.31
-
- It is now known that glutamate acts on its receptor via
a nitric oxide mechanism.32 Overstimulation of the glutamate receptor
can produce an accumulation of reactive nitrogen species, resulting in
the generation of several species of dangerous free radicals, including
peroxynitrite. There is growing evidence that, at least in part, this is
how excess glutamate damages nerve cells.33 In a multitude of studies,
a close link has been demonstrated between excitotoxicity and free radical
generation.34- 37
-
- Others have shown that certain free radical scavengers
( antioxidants), have successfully blocked excitotoxic destruction of neurons.
For example, vitamin E is known to completely block glutamate toxicity
in vitro.38 Whether it will be as efficient in vivo is not known. But,
it is interesting in light of the recent observations that vitamin E combined
with other antioxidant vitamins slows the course of Alzheimer's disease
and has been suggested to reduce the rate of advance in a subgroup Parkinson's
disease patients as well. In the DATATOP study of the effect of alpha-tocopherol
alone, no reduction in disease progression was seen. The problem with
this study was the low dose that was used and the fact that the DL-alpha-tocopherol
used is known to have a much lower antioxidant potency than D-alpha-tocopherol.
Stanley Fahn found that a combination of D-alpha-tocopherol and ascorbic
acid in high doses reduced progression of the disease by 2.5 years.39 Tocotrienol
may have even greater benefits, especially when used in combination with
other antioxidants. There is some clinical evidence, including my own observations,
that vitamin E also slows the course of ALS as well, especially in the
form of D- alpha-tocopherol. I would caution that antioxidants work best
in combination and when use separately can have opposite, harmful, effects.
That is, when antioxidants, such as ascorbic acid and alpha tocopherol,
become oxidized themselves, such as in the case of dehydroascorbic acid,
they no longer protect, but rather act as free radicals themselves. The
same is true of alpha-tocopherol.40
-
- Again, it should be realized that excessive glutamate
stimulation triggers a chain of events that in turn sparks the generation
of large numbers of free radical species, both as nitrogen and oxygen species.
These free radicals have been shown to damage cellular proteins ( protein
carbonyl products) and DNA . The most immediate DNA damage is to the mitochondrial
DNA, which controls protein expression within that particular cell and
its progeny, producing rather profound changes in cellular energy production.
It is suspected that at least some of the neurodegenerative diseases, Parkinson's
disease in particular, are affected in this way.41 Chronic free radical
accumulation would result in an impaired functional reserve of antioxidant
vitamins/minerals and enzymes, and thiol compounds necessary for neural
protection. Chronic unrelieved stress, chronic infection, free radical
generating metals and toxins, and impaired DNA repair enzymes all add to
this damage.
-
- We know that there are four main endogenous sources of
oxidants:
-
- 1. Those produced naturally from aerobic metabolism of
glucose. 2. Those produced during phagocytic cell attack on bacteria, viruses,
and parasites, especially with chronic infections. 3. Those produced during
the degradation of fatty acids and other molecules that produce 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 the exposure
of tissues to free iron, especially in the presence of ascorbate. Unfortunately,
iron is one mineral heavily promoted by the health industry, and is frequently
added to many foods, especially breads and pastas. Copper is also a powerful
free radical generator and has been shown to be elevated within the substantia
nigra of Parkinsonian brains.42
-
- What has been shown in all these studies is a direct
connection between excitotoxicity and free radical generation in a multitude
of diseases and disorders such as seizures, strokes, brain trauma,viral
infections, and neurodegenerative diseases. Interestingly, free radicals
have also been shown to prevent glutamate uptake by astrocytes as well,
which would significantly increase extracellular glutamate levels.43 This
creates a vicious cycle that will multiply any resulting damage and malfunctioning
of neurophysiological systems, such as plasticity.
-
- The Blood-Brain Barrier
-
- One of the MSG industry's chief arguments for the safety
of their product is that glutamate in the blood cannot enter the brain
because of the blood-brain barrier ( BBB), a system of specialized capillary
structures designed to exclude toxic substance from entering the brain.
There are several criticisms of their defense. For example, it is known
that the brain, even in the adult, has several areas that normally do not
have a barrier system, called the circumventricular organs. These include
the hypothalamus, the subfornical organ, organium vasculosum, area postrema,
pineal gland, and the subcommisural organ. Of these, the most important
is the hypothalamus, since it is the controlling center for all neuroendocrine
regulation, sleep wake cycles, emotional control, caloric intake regulation,
immune system regulation and regulation of the autonomic nervous system.
As stated, glutamate is the most important neurotransmitter in the hypothalamus.
Therefore, careful regulation of blood levels of glutamate is very important,
since high blood concentrations of glutamate would be expected to increase
hypothalamic levels as well. One of the earliest and most consistent findings
with exposure to MSG is damage to an area of the hypothalamus known as
the arcuate nucleus.This small hypothalamic nucleus controls a multitude
of neuroendocrine functions, as well as being intimately connected to several
other hypothalamic nuclei. It has also been demonstrated that high concentrations
of blood glutamate and aspartate ( from foods) can enter the so-called
"protected brain" by seeping through the unprotected areas, such
as the hypothalamus or other circumventricular organs.
-
- Another interesting observation is that chronic elevations
of blood glutamate can even seep through the normal blood-brain barrier
when these high concentrations are maintained over a long period of time.44
This would be the situation seen when individuals consume, on a daily basis,
foods high in the excitotoxins - MSG, aspartame and L-cysteine. Most experiments
cited by the defenders of MSG safety were conducted to test the efficiency
of the BBB acutely. In nature, except in the case of metabolic dysfunction
( such as with ALS), glutamate and aspartate levels are not normally elevated
on a continuous basis. Sustained elevations of these excitotoxins are peculiar
to the modern diet. ( and in the ancient diets of the Orientals, but not
in as high a concentration.)
-
- An additional critical factor ignored by the defenders
of excitotoxin food safety is the fact that many people in a large population
have disorders known to alter the permeability of the blood-brain barrier.
The list of condition associated with barrier disruption include: hypertension,
diabetes, ministrokes, major strokes, head trauma, multiple sclerosis,
brain tumors, chemotherapy, radiation treatments to the nervous system,
collagen-vascular diseases ( lupus), AIDS, brain infections, certain drugs,
Alzheimer's disease, and as a consequence of natural aging. There may
be many other conditions also associated with barrier disruption that are
as yet not known.
-
- When the barrier is dysfunctional due to one of these
conditions, brain levels of glutamate and aspartate reflect blood levels.
That is, foods containing high concentrations of these excitotoxins will
increase brain concentrations to toxic levels as well. Take for example,
multiple sclerosis. We know that when a person with MS has an exacerbation
of symptoms, the blood-brain barrier near the lesions breaks down, leaving
the surrounding brain vulnerable to excitotoxin entry from the blood, i.e.
the diet.45 But, not only is the adjacent brain vulnerable, but the openings
act as points of entry, eventually exposing the entire brain to potentially
toxic levels of glutamate. Several clinicians have remarked that their
MS patients were made worse following exposure to dietary excitotoxins.
I have seen this myself. It is logical to assume that patients with the
other neurodegenerative disorders, such as Alzheimer's disease, Parkinson's
disease, and ALS will be made worse on diets high in excitotoxins. Barrier
disruption has been demonstrated in the case of Alzheimer's disease.46
-
- Recently, it has been shown that not only can free radicals
open the blood-brain barrier, but excitotoxins can as well.47 In fact,
glutamate receptors have been demonstrated on the barrier itself.48 In
a carefully designed experiment, researchers produced opening of the blood-brain
barrier using injected iron as a free radical generator. When a powerful
free radical scavenger ( U-74006F) was used in this model, opening of the
barrier was significantly blocked. But, the glutamate blocker MK-801 acted
even more effectively to protect the barrier. The authors of this study
concluded that glutamate appears to be an important regulator of brain
capillary transport and stability, and that overstimulation of NMDA ( glutamate)
receptors on the blood-brain barrier appears to play an important role
in breakdown of the barrier system. What this also means is that high levels
of dietary glutamate or aspartate may very well disrupt the normal blood-brain
barrier, thus allowing more glutamate to enter the brain, creating a vicious
cycle.
-
- Relation to Cellular Energy Production
-
- Excitotoxin damage is heavily dependent on the energy
state of the cell.49 Cells with a normal energy generation systems are
very resistant to such toxicity. When cells are energy deficient, no matter
the cause - hypoxia, starvation, metabolic poisons, hypoglycemia - they
become infinitely more susceptible to excitotoxic injury or death. Even
normal concentrations of glutamate are toxic to energy deficient cells.
-
- It is known that in many of the neurodegenerative disorders,
neuron energy deficiency often precedes the clinical onset of the disease
by years, if not decades.50 This has been demonstrated in the case of Huntington
disease and Alzheimer's disease using the PET scanner, which measures brain
metabolism. In the case of Parkinson's disease, several groups have demonstrated
that one of the early deficits of the disorder is an impaired energy production
by the complex I group of enzymes within the mitochondria of the substantia
nigra.51,52 Interestingly, it is known that the complex I system is very
sensitive to free radical damage.
-
- Recently, it has been shown that when striatal neurons
are exposed to microinjected excitotoxins there is a dramatic, and rapid
fall in energy production by these neurons. CoEnzyme Q10 has been shown,
in this model, to restore energy production but not to prevent cellular
death. But when combined with niacinamide, both cellular energy production
and neuron protection is seen.53 I recommend for those with neurodegenerative
disorders, a combination of CoQ10, acetyl-L carnitine, niacinamide, riboflavin,
methylcobalamin, and thiamine.
-
- One of the newer revelation of modern molecular biology,
is the discovery of mitochondrial diseases, of which cellular energy deficiency
is a hallmark. In many of these disorders, significant clinical improvement
has been seen following a similar regimen of vitamins combined with CoQ10
and L-carnitine.54 Acetyl L-carnitine enters the brain in higher concentrations
and also increases brain acetylcholine, necessary for normal memory function.
While these particular substances have been found to significantly boost
brain energy function they are not alone in this important property. Phosphotidyl
serine, Ginkgo Biloba, vitamin B12, folate, magnesium, Vitamin K and several
others are also being shown to be important.
-
- While mitochrondial dysfunction is important in explaining
why some are more vulnerable to excitotoxin damage than others, it does
not explain injury in those with normal cellular metabolism. There are
several conditions under which energy metabolism is impaired. We know,
for example, approximately one third of Americans suffer from reactive
hypoglycemia. That is, they respond to a meal composed of either simple
sugars or carbohydrates (that are quickly broken down into simple sugars
, i.e. a high glycemic index.) by secreting excessive amounts of insulin.
This causes a dramatic lowering of the blood sugar.
-
- When the blood sugar falls, the body responds by releasing
a burst of epinephrine from the adrenal glands, in an effort to raise the
blood sugar. We feel this release as nervousness, palpitations of our heart,
tremulousness, and profuse sweating. Occasionally, one can have a slower
fall in the blood sugar that will not produce a reactive release of epinephrine,
thereby producing few symptoms. This can be more dangerous, since we are
unaware that our glucose reserve is falling until we develop obvious neurological
symptoms, such as difficulty thinking and a sensation of lightheadedness.
-
- The brain is one of the most glucose dependent organs
known, since it has a limited ability to metabolize other substrates such
as fats. There is some evidence that several of the neurodegenerative diseases
are related to either excessive insulin release, as with Alzheimer's disease,
or impaired glucose utilization, as we have seen in the case of Parkinson's
disease and Huntington's disease.55
-
- It is my firm belief, based on clinical experience and
physiological principles, that many of these diseases occur primarily in
the face of either reactive hypoglycemia or " brain hypoglycemia",
a condition where the blood sugar is normal and the brain is hypoglycemic
in isolation. In at least two well conducted studies it was found that
pure Alzheimer's dementia was rare in those with normal blood sugar profiles,
and that in most cases Alzheimer's patients had low blood sugars, and high
CSF ( cerebrospinal fluid) insulin levels.56,57 In my own limited experience
with Parkinson's and ALS patients I have found a disproportionately high
number suffering from reactive hypoglycemia.
-
- I found it interesting that several ALS patients have
observed an association between their symptoms and gluten. That is, when
they adhere to a gluten free diet they improve clinically. It may be that
by avoiding gluten containing products, such as bread, crackers, cereal,
pasta ,etc, they are also avoiding products that are high on the glycemic
index, i.e. that produce reactive hypoglycemia. Also, all of these food
items are high in free iron. Clinically, hypoglycemia will worsen the symptoms
of most neurological disorders. We know that severe hypoglycemia can, in
fact, mimic ALS both clinically and pathologically.58 It is also known
that many of the symptoms of Alzheimer's disease resemble hypoglycemia,
as if the brain is hypoglycemic in isolation.
-
- In studies of animals exposed to repeated mild episodes
of hypoxia ( lack of brain oxygenation), it was found that such accumulated
injuries can trigger biochemical changes that resemble those seen in Alzheimer's
patients.59 One of the effects of hypoxia is a massive release of glutamate
into the space around the neuron. This results in rapid death of these
sensitized cells. As we age, the blood supply to the brain is frequently
impaired, either because of atherosclerosis or repeated syncopal episodes,
leading to short periods of hypoxia. Hypoglycemia produces lesions very
similar to hypoxia and via the same glutamate excitotoxic mechanism. In
fact, recent studies of diabetics suffering from repeated episodes of hypoglycemia
associated with over medication with insulin, demonstrate brain atrophy
and dementia.60
-
- Another cause of isolated cerebral hypoglycemia is impaired
transport of glucose into the brain across the blood-brain barrier. It
is known that glucose enters the brain by way of a glucose transporter,
and that in several conditions this transporter is impaired. This includes
aging, arteriosclerosis, and Alzheimer's disease.61,62 This is especially
important in the diabetic since prolonged elevation of the blood sugar
produces a down-regulation of the glucose transporter and a concomitant
" brain hypoglycemia" that is exacerbated by repeated spells
of peripheral hypoglycemia common to type I diabetics.
-
- With aging, one sees several of these energy deficiency
syndromes, such as mitochondrial injury, impaired cerebral blood flow,
enzyme dysfunction, and impaired glucose transportation, develop simutaneously.
This greatly magnifies excitotoxicity, leading to accelerated free radical
injury and a progressively rapid loss of cerebral function and profound
changes in cellular energy production.63 It is suspected that at least
in some of the neurodegenerative diseases, Alzheimer's dementia and Parkinson's
disease in particular, this series of events plays a major pathogenic role.64
Chronic free radical accumulation would also result in an impaired functional
reserve of antioxidant vitamins/minerals, antioxidant enzymes ( SOD, catalase,
and glutathione peroxidase), and thiol compounds necessary for neural protection.
Chronic unrelieved stress, chronic infection, free radical generating
metals and toxins, and impaired DNA repair enzymes all add to this damage.
-
- It is estimated that the number of oxidative free radical
injuries to DNA number about 10,000 a day in humans.65 Under conditions
of cellular stress this may reach several hundred thousand.Normally, these
injuries are repaired by special DNA repair enzymes. It is known that as
we age these repair enzymes decrease or become less efficient.66 Also,
some individuals are born with deficient repair enzymes from birth as,
for example, in the case of xeroderma pigmentosum. Recent studies of Alzheimer's
patients also demonstrate a significant deficiency in DNA repair enzymes
and high levels of lipid peroxidation products in the affected parts of
the brain.67,68 It is also important to realize that the hippocampus of
the brain, most severely damaged in Alzheimer's dementia, is one of the
most vulnerable areas of the brain to low glucose supply as well as low
oxygen supply. That also makes it very susceptible to glutamate/ free radical
toxicity.
-
- Another interesting finding is that when cells are exposed
to glutamate they develop certain inclusions ( cellular debris) that not
only resembles the characteristic neurofibrillary tangles of Alzheimer's
dementia, but are immunologically identical as well.69 Similarly, when
experimental animals are exposed to the chemical MPTP, they not only develop
Parkinson's disorder, but the older animals develop the same inclusions
( Lewy bodies) as see in human Parkinson's.70 There is growing evidence
that protracted glutamate toxicity leads to a condition of receptor loss
characteristic of neurodegeneration.71 This receptor loss produces a state
of disinhibition that magnifies excitotoxicity during the later stage of
the neurodegenerative process.
-
- Special Functions of Ascorbic Acid
-
- The brain contains one of the highest concentrations
of ascorbic acid in the body. Most are aware of ascorbic acid's function
in connective tissue synthesis and as a free radical scavenger. But, ascorbic
acid has other functions that make it rather unique.
-
- In man, we know that certain areas of the brain have
very high concentrations of ascorbic acid, such as the nucleus accumbens
and hippocampus. The lowest levels are seen in the substantia nigra.72
These levels seem to fluctuate with the electrical activity of the brain.
Amphetamine acts to increase ascorbic acid concentration in the corpus
striatum ( basal ganglion area) and decrease it in the hippocampus, the
memory imprint area of the brain. Ascorbic acid is known to play a vital
role in dopamine production as well.
-
- One of the more interesting links has been between the
secretion of the glutamate neurotransmitter by the brain and the release
of ascorbic acid into the extracellular space.73 This release of ascorbate
can also be induced by systemic administration of glutamate or aspartate,
as would be seen in diets high in these excitotoxins . The other neurotransmitters
do not have a similar effect on ascorbic acid release. This effect appears
to be an exchange mechanism. That is, the ascorbic acid and glutamate exchange
places. Theoretically, high concentration of ascorbic acid in the diet
could inhibit glutamate release, lessening the risk of excitotoxic damage.
Of equal importance is the free radical neutralizing effect of ascorbic
acid.
-
- There is now substantial evidence that ascorbic acid
modulates the electrophysiological as well as behavioral functioning of
the brain.74 It also attenuates the behavioral response of rats exposed
to amphetamine, which is known to act through an excitatory mechanism.75
In part, this is due to the observed binding of ascorbic acid to the glutamate
receptor. This could mean that ascorbic acid holds great potential in treating
disease related to excitotoxic damage. Thus far, there are no studies relating
ascorbate metabolism in neurodegenerative diseases. There is at least one
report of ascorbic acid deficiency in guineas pigs producing histopathological
changes similar to ALS.76
-
- It is known that as we age there is a decline in brain
levels of ascorbate. When accompanied by a similar decrease in glutathione
peroxidase, we see an accumulation of H202 and hence, elevated levels of
free radicals and lipid peroxidation. In one study, it was found that with
age not only does the extracellular concentration of ascorbic acid decrease
but the capacity of the brain ascorbic acid system to respond to oxidative
stress is impaired as well.77
-
- In terms of its antioxidant activity, vitamin C and E
interact in such a way as to restore each others active antioxidant state.
Vitamin C scavenges oxygen radicals in the aqueous phase and vitamin E
in the lipid, chain breaking, phase. The addition of vitamin C suppresses
the oxidative consumption of vitamin E almost totally, probably because
in the living organism the vitamin C in the aqueous phase is adjacent to
the lipid membrane layer containing the vitamin E.
-
- When combined, the vitamin C is consumed faster during
oxidative stress than vitamin E. Once the vitamin C is totally consumed,
vitamin E begins to be depleted at an accelerated rate. N-acetyl-L-cysteine
and glutathione can reduce vitamin E consumption as well, but less effectively
than vitamin C. The real danger is when vitamin C is combined with iron.
This is because the free iron oxidizes the ascorbate to produce the free
radical dehydroxyascorbate. Alpha-lipoic acid acts powerfully to keep the
ascorbate and tocopherol in the reduced state (antioxidant state). As we
age, we produce less of the transferrin transport protein that normally
binds free iron. As a result, older individuals have higher levels of free
iron within their tissues, including brain, and are therefore at greater
risk of widespread free radical injury.
-
- Neurodevelopment:
-
- Recent studies have shown that glutamate plays a vital
role in the development of the nervous system, especially as regards neuronal
survival, growth and differentiation, development of circuits and cytoarchitecture.78
For example, it is known that deficiencies of glutamate in the brain during
neurogenesis can result in maldevelopment of the visual cortices and may
play a role in the development of schizophrenia.79 Likewise, excess glutamate
can cause neural pathways to produce improper connections, a process I
call " miswiring of the brain". Excess glutamate during embryogenesis
has been shown to reduce dendritic length and suppress axonal outgrowth
in hippocampal neurons. It is interesting to note that glutamate can produce
classic toxicity in the immature brain even before the glutamate receptors
develop. High glutamate levels can also affect astroglial proliferation
as well as neuronal differentiation. It appears to act via the phosphoinositide
protein kinase C pathway.
-
- It has been shown that during brain development there
is an overgrowth of neuronal connections and cellularity, and that at this
stage there is a peak in brain glutamate levels whose function it is to
remove excess connections and neuronal overexpression. This has been referred
to as " pruning". Importantly, glutamate excess during synaptogenesis
and pathway development has been shown to cause abnormal connections in
the hypothalamus that can lead to later endocrinopathies.80
-
- In general, toxicological injury in the developing fetus
carries the greatest risk during the first two trimesters. But, this is
not so for the brain, which undergoes a spurt of growth that begins during
the third trimester and continues at least two years after birth. Dendritic
growth is maximal in the late fetal period to one year of age, but may
continue at a slower pace for several more years. Neurotransmitter development
also begins during the late fetal period but continues for as long as four
years after birth. This means that alterations in dietary glutamate and
aspartate are especially dangerous to the fetus during pregnancy and for
several years after birth. The developing brain's succeptability to excitotoxicity
varies , since each brain region has a distinct developmental profile.
The type of excitotoxin also appears to matter. For example, kianate is
non-toxic to the immature brain but extremely toxic to the mature brain.
The glutamate agonist, NMDA, is especially toxic up to postnatal day seven
while quisqualate and AMPA have peak toxicity from postnatal day seven
through fourteen. L-cysteine is a powerful excitotoxin on the immature
brain.
-
- Myelination can also be affected by neurotoxins. In general,
excitotoxic substances affect dendrites and neurons more than axons but
axon demyelination has been demonstrated. During the myelination process,
each fiber tract has its own spatiotemporal pattern of development, accompanied
by significant biochemical changes, especially in lipid metabolism. More
recent studies have shown an even more complicated pattern of CNS myelination
than previously thought. This is of importance especially as regards the
widespread use of aspartame, because of this triple toxin's effects on
neuronal proteins and DNA. Of special concern is aspartame's methanol component
and its breakdown product, formaldehyde.81 Also, it is known that the aspartate
moiety undergoes spontanous racemization in hot liquids to form D-aspartate,
which has been associated with tau proteins in Alzheimer's disease.82,83
-
- As you can see, the development of the brain is a very
complex process that occurs in a spatial and temporal sequence that is
carefully controlled by biochemical, structural, as well as neurophysiological
events. Even subtle changes in these parameters can produce ultimate changes
in brain function that may vary from subtle alteration in behavior and
learning to autism, attention deficit disorder and violence dyscontrol.84,85,86
-
- Experiments in which infant animals were exposed to MSG,
have demonstrated significant neurobehavioral deficits.87,88 Other studies
have shown that when pregnant female animals were fed MSG their offspring
demonstrated normal simple learning but showed significant deficits in
complex learning, accompanied by profound reductions in several forebrain
neurotransmitters.89,90 In human this would mean that during infancy and
early adolescence learning would appear normal, but with entry into a more
advance education level, learning would be significantly impaired. In
several ways, this animal model resembles ADD and ADHD in humans. Kubo
and co-workers found that neonatal glutamate could severely injure hippocampal
CA1 neurons and dendrites and, as a result, impair discriminative learning
in rats.91
-
- It is also important to note that neonatal exposure to
MSG has been shown to cause significant alterations in neuroendocrine function
that can be prolonged.92,93 By acting on the hypothalamus and its connections
to the remainder of the limbic connections, excitotoxins can profoundly
affect behavior.
-
- Conclusion
-
- In this brief discussion of a most complicated and evolving
subject I have had to omit several important pieces of the puzzle. For
example, I have said little about the functional components of the receptor
systems, the glutamate transporter and its relation to ALS and Alzheimer's
dementia, receptor decay with aging and disease, membrane effects of lipid
peroxidation products, membrane fluidity, effects of chronic inflammation
on the glutamate/free radical cycle, stress hormones and excitotoxicity,
the role of insulin excess on the eicosanoid system, or the detailed physiology
of the glutamatergic system. I have also only briefly alluded to the toxicity
of aspartame and omitted its strong connection to brain tumor induction.
-
- But, I have tried to show the reader that there is a
strong connection between dietary and indogenous excitotoxin excess and
neurological dysfunction and disease. Many of the arguments by the food
processing industry has been shown to be false. For example, that dietary
glutamate does not enter the brain because of exclusion by the blood-brain
barrier, has been shown to be wrong, since glutamate can enter by way of
the unprotected areas of the brain such as the circumventricular organs.
Also, as we have seen, chronic elevations of blood glutamate can breech
the intact blood-brain barrier. In addition, there are numerous conditions
under which the barrier is made incompetent.
-
- As our knowledge of the pathophysiology and biochemistry
of the neurodegenerative diseases increases, the connection to excitotoxicity
has become stonger.94 This is especially so with the interrelationship
between excitotoxicity and free radical generation and declining energy
production with aging. Several factors of aging have been shown to magnify
this process. For example, as the brain ages its iron content increases,
making it more susceptible to free radical generation. Also , aging changes
in the blood brain barrier, micovascular changes leading to impaired blood
flow, free radical mitochondrial injury to energy generating enzymes, DNA
adduct formation, alterations in glucose and glutamate transporters and
free radical and lipid peroxidation induced alterations in the neuronal
membranes all act to make the aging brain increasingly susceptible to excitotoxic
injury.
-
- Over a lifetime of free radical injury due to chronic
stress, infections, trauma, impaired blood flow, hypoglycemia, hypoxia
and poor antioxidant defenses secondary to poor nutritional intake, the
nervous system is significantly weakened and made more susceptible to further
excitotoxic injury. We known that a loss of neuronal energy generation
is one of the early changes seen with the neurodegenerative diseases. This
occurs long before clinical disease develops. But, even earlier is a loss
of neuronal glutathione functional levels.
-
- I included the material about the special function of
ascorbic acid because few are aware of the importance of adequate ascorbate
levels for CNS function and neural protection against excitotoxicity. As
we have seen, it plays a vital role in neurobehavioral regulation and the
dopaminergic system as well,which may link ascorbate supplementation to
improvements in schizophrenia.
-
- Our knowledge of this process opens up new avenues for
treatment as well as prevention of excitotoxic injury to the nervous system.
For example, there are many nutritional ways to improve CNS antioxidant
defenses and boost neuronal energy generation, as well as improve membrane
fluidity and receptor integrity. By using selective glutamate blocking
drugs or nutrients, one may be able to alter some of the more devastating
effects of Parkinson's disease. For example, there is evidence that dopamine
deficiency causes a disinhibition ( overactivity) of the subthalamic nucleus
and that this may result in excitotoxic injury to the substantia nigra.95
By blocking the glutamatergic neurons in this nucleus, one may be able
to reduce this damage. There is also evidence that several nutrients can
significantly reduce excitotoxicity. For example, combinations of coenzyme
Q10 and niacinamide have been shown to protect against striatal excitotoxic
lesions. Methylcobolamine, phosphotidylserine, picnogenol and acetyl-L-carnitine
all protect against excitotoxicity as well.
-
- Of particular concern is the toxic effects of these excitotoxic
compounds on the developing brain. It is well recognized that the immature
brain is four times more sensitive to the toxic effects of the excitatory
amino acids as is the mature brain.This means that excitotoxic injury is
of special concern from the fetal stage to adolescence. There is evidence
that the placenta concentrates several of these toxic amino acids on the
fetal side of the placenta. Consumption of aspartame and MSG containing
products by pregnant women during this critical period of brain formation
is of special concern and should be discouraged. Many of the effects,
such as endocrine dysfunction and complex learning, are subtle and may
not appear until the child is older. Other hypothalamic syndromes associated
with early excitotoxic lesions include immune alterations and violence
dyscontrol.
-
- Over 100 million American now consume aspartame products
and a greater number consume products containing one or more excitotoxins.
There is sufficient medical literature documenting serious injury by these
additives in the concentrations presently in our food supply to justify
warning the public of these dangers. The case against aspartame is especially
strong.
-
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