Part 9 Excitotoxins, Neurodegeneration and Neurodevelopment

Part 9 Excitotoxins, Neurodegeneration and Neurodevelopment
By Russell L. Blaylock, M.D

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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Part 8 Excitotoxins, Neurodegeneration and Neurodevelopment

Part 8 Excitotoxins, Neurodegeneration and Neurodevelopment
By Russell L. Blaylock, M.D

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.

Part 5 Excitotoxins, Neurodegeneration and Neurodevelopment

Excitotoxins, Neurodegeneration and Neurodevelopment
By Russell L. Blaylock, M.D

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.49 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.

Part 3 Excitotoxins, Neurodegeneration and Neurodevelopment

Excitotoxins, Neurodegeneration and NeurodevelopmentBy Russell L. Blaylock, M.D



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.

Part 2 of Excitotoxins, Neurodegeneration and Neurodevelopment

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.