Vol.3, # 32
August 26, 2006

Q: What are excitotoxins? - Layperson

A: These are substances, usually acidic amino acids, that react with specialized receptors in the brain neurons in such a way that they become very excited and fire their impulses very rapidly until they reach a state of "extreme exhaustion". Several hours later these neurons suddenly die as if the cells were excited to death. H Vegetable Protein

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. 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. 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.  

More recent molecular studies have disclosed the mechanism of this destruction in some detail. 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.

Some foods advertise “No MSG”, or No added MSG”, but actually contain large amounts of a hidden MSG derivative, called “free glutamate”. Many people experience adverse reactions but are not aware that the cause may be exposure to this substance, free glutamate, which is created in manufacturing processes. When any product contains at least 79% free glutamic acid it must be called MSG. Quantities of less than this amount, do not fall under MSG labeling restrictions, and can be called any number of innocent sounding names, such as “natural flavoring”. In larger quantities, free glutamate is toxic to everyone, but for those who cannot metabolize it effectively, even very small doses can act like a poison. MSG stimulates or damages glutamate receptors, making them more sensitive to subsequent ingestion of MSG. Science suggests that free glutamates may act as a “slow neurotoxin” with damage, such as dementia, only becoming apparent years later.

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.

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.  

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.  

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. 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 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.  

One interesting study found 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 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.

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. 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. Antioxidants work best in combination and when used 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.  

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.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. 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. 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, 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.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. 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. 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. 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.  

It is my firm belief, based on clinical experience and physiological principles, that many of these diseases occur primarily in the face of either reactive hypoglycemia or " brain hypoglycemia", a condition where the blood sugar is normal and the brain is hypoglycemic in isolation. In at least two well conducted studies it was found that pure Alzheimer's dementia was rare in those with normal blood sugar profiles, and that in most cases Alzheimer's patients had low blood sugars, and high CSF ( cerebrospinal fluid) insulin levels.55-57   In my own limited experience with Parkinson's and ALS patients I have found a disproportionately high number suffering from reactive hypoglycemia.

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.  

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.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. 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. 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.  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. 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/ 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. 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. There is growing evidence that protracted glutamate toxicity leads to a condition of receptor loss characteristic of neurodegeneration. 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.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 ascorbate. When accompanied by a similar decrease in glutathione peroxidase, we see an accumulation of h302 and hence, elevated levels of free radicals and lipid peroxidation. In one study, it was found that with age not only does the extracellular concentration of ascorbic acid decrease but the capacity of the brain ascorbic acid system to respond to oxidative stress is impaired as well.  

In terms of its antioxidant activity, vitamin C and E interact in such a way as to restore each others active antioxidant state. Vitamin C scavenges oxygen radicals in the aqueous phase and vitamin E in the lipid, chain breaking, phase. The addition of vitamin C suppresses the oxidative consumption of vitamin E almost totally, probably because in the living organism the vitamin C in the aqueous phase is adjacent to the lipid membrane layer containing the vitamin E.

When combined, the vitamin C is consumed faster during oxidative stress than vitamin E. Once the vitamin C is totally consumed, vitamin E begins to be depleted at an accelerated rate. N-acetyl-L-cysteine and glutathione can reduce vitamin E consumption as well, but less effectively than vitamin C. The real danger is when vitamin C is combined with iron. This is because the free iron oxidizes the ascorbate to produce the free radical dehydroxyascorbate. Alpha-lipoic acid acts powerfully to keep the ascorbate and tocopherol in the reduced state (antioxidant state). As we age, we produce less of the transferrin transport protein that normally binds free iron. As a result, older individuals have higher levels of free iron within their tissues, including brain, and are therefore at greater risk of widespread free radical injury.


Recent studies have shown that glutamate plays a vital role in the development of the nervous system, especially as regards neuronal survival, growth and differentiation, development of circuits and cytoarchitecture. 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. Likewise, excess glutamate can cause neural pathways to produce improper connections. 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. 

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. 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. 

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. 

Experiments in which infant animals were exposed to MSG, have demonstrated significant neurobehavioral deficits. 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. 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.  

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. By acting on the hypothalamus and its connections to the remainder of the limbic connections, excitotoxins can profoundly affect behavior.

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.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.

In short, our mother's advice and meals were best-consume fresh, unprocessed foods and drinks as much as possible (Eat your fruits, vegetables, meats, and grains). If the ingredients on the label do not appear to be something that could be eaten by itself, then it is probably something not good for you.


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DISCLAIMER:  The information in this column, is NOT intended to diagnose and/or treat any health related issues and is provided solely for informational purposes only. Consult the appropriate healthcare professional before making any changes to your healthcare regime. Even what may seem like simple changes in the diet for example, can interact with, and alter, the efficiency of medications and/or the body's response to the medications. Many herbs and supplements exert powerful medicinal effects. Neither the author, nor the website designers, assume any responsibility for the reader's use or misuse of this information.

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