ABSTRACT
In the United States today, there is an ever-increasing number of Americans that are afflicted with neurodegenerative diseases. Because the development of these diseases remains idiopathic, we must consider that diet and environmental factors play a major role. Due to the limited information on excitatory amino acid buildup in the body and the negative and degenerative effect it has on the human nervous system, medical professionals are limited when it comes to proper diagnosis. Over the past four decades, more and more people have unknowingly consumed excitotoxins that have been proven to cause brain damage, perhaps even brain lesions and tumors. There is now enough epidemiological evidence to point a finger to an environmental etiology for neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Multiple Sclerosis (MS), and amyotrophic lateral sclerosis (ALS). That environmental factor is Aspartame. Aspartame (C14H18N2O5) is a compound of three components: aspartic acid, phenylalanine, and methanol. Aspartame causes neurons to die and mimics degenerative brain diseases.
In 1964, under the aegis of G.D. Searle and company, a group that included Dr. Robert Mazur, Dr. James Schlatter, Dr. Arthur Goldkemp, and the Imperial Chemical Company was formed to work on an ulcer drug that would act as an inhibitor to the gastrointestinal secretory, Gastrin (Stegink, 1984; Faber, 1989). While determining the strength or biological activity of that substance, an intermediate chemical was synthesized. That new chemical, aspartylphenylalanine-methl-ester, was given the name Aspartame.
Figure 1. The chemical structure of Aspartame- Aspartame consists of three components: aspartic acid (a nonessential amino acid), phenylalanine (an essential amino acid), and methyl ester which is metabolized to free methyl alcohol, or methanol.
In December of 1965, Dr. Schlatter was working with Aspartame during the process known as recrystallization, a procedure for purifying compounds. Dr. Schlatter was recrystalling Aspartame from ethanol, when the mixture spilled onto the outside of the flask. Some of the powder got onto his fingers. He licked his fingers in order to pick up a piece of paper and suddenly became aware of a very strong, sweet taste. His discovery of that powder was reported in 1966 with no mention of the sweet taste (Furia, 1972). It was Dr. Mazur who reported this discovery of an artificial sweetener in the Journal of the Amercian Chemical Society in 1969 (Mazur, 1969).
Dr. Harry Waisman, a biochemist, was a Professor of Pediatrics and the Director of the University of Wisconsin's Joseph P. Kennedy Jr. Memorial Laboratory of Mental Retardation Research when he was contracted by G.D. Searle to conduct a study of the effects of Aspartame on primates. The study began on January 15, 1970 and was terminated on April 25, 1971 after Dr. Waisman’s death in March 1971. The study involved seven infant monkeys who were given Aspartame with milk. The monkeys were divided into three groups. The low dose group was given 1.0 g/kg of Aspartame in their milk. A medium dose group, 3.0 g/kg. and a high dose group 4-6 g/kg were also fed the same milk laced with Aspartame and administered orally however, the high dose group did not consume intended levels of Aspartame during the study. This was thought to be due to the overt sweetness of the Aspartame (200 times greater than sugar). Thus, researchers involved in this study concluded, the high-dose group actually ingested approximately as much Aspartame as the medium-dose group. Because of Dr. Waisman’s death early on, the low-dose group of monkeys were pulled from this study at about 200 days-prior to when brain seizures commenced for the medium and high-dose groups (Stoddard, 1995; Merrill, 1977; Graves, 1984; Congressional Record, 1985; Gross, 1976)
All medium and high dose monkeys showed increased phenylalanine levels in their blood. All medium and high dose monkeys exhibited brain seizures, starting about seven months into the experiment. The study reports "All animals in the medium and high dosage groups exhibited seizure activity. Seizures were observed for the first time following 218 days of treatment. The seizures were of the grand mal type. One monkey, m38, of the high dose group, died after 300 days of treatment. The cause of death was not determined" (Rao, McConnell, & Waisman, p. 9). After 300 days, one monkey died and five others had grand mal seizures. These results were never shown to the Food and Drug Administration (FDA) when G.D. Searle submitted its findings. In fact, G.D. Searle denied any involvement whatsoever in the study (Stoddard, 1995).
In 1970, Neuroscientist and researcher, Dr. John W. Olney found that oral intake of aspartic acid caused brain damage in mice, and he informed G.D. Searle of his findings (Olney, 1970). He revealed in his findings that the transport of excitotoxins across the blood brain barrier and within the cerebral spinal fluid (CSF) caused several reactions to occur. 1.) The excitotoxins stimulate the nerves to fire excessively. 2.) The normal enzyme actions required to offset the induced, repeated firing of these neurons are negated by the phenylalanine and aspartic acid. 3.) The energy system for the required enzyme reactions becomes compromised from depleted intracellular ATP stores. 4.) The presence of formaldehyde alters intracellular calcium (Ca+) uptake. 5.) Damage to cellular mitochondria, destruction of the cellular wall, and the subsequent release of free radicals potentiates oxidative stress and neurodegeneration (Olney, 1970).
Dr. Olney also expressed that these toxic by-products instigate secondary damage by increasing capillary permeability, which continues to destroy the surrounding nerve and glial cells. This expedites enzyme reactions, and promotes DNA structural defects (Olney, 1970; Bowen & Evangelista, 2002).
Dr. Olney reported that cellular death occurs over 1 to 12 hours. This does not include the long-term or cumulative effects of other metabolites. With each test he conducted, he discovered that the dead cells leave behind lesions. His evidence showed that the following disease states could be clinically identified by their corresponding anatomic nerve fiber, or nerve bundle damage:
1) Aqueduct of Sylvius - Hydrocephalus
2) White matter bundles - Multiple Sclerosis (MS)
3) Pyramids/Basal Ganglia - Parkinson's Disease
4) Lateral corticospinal tracts of spinal cord and bulbar nuclei - Amyotrophic lateral sclerosis (Lou Gehrig's)
5) Destruction of hypothalamic regions - Neuro-endocrine disorders, obesity, psychogenic disorders (behavior, anger) malfunction of autonomic nervous system, and immune suppression. (Bowen and Evangelista, 2002)
G.D. Searle responded by hiring Dr. Ann Reynolds, a researcher who had done research for the Glutamate (MSG) Association, to confirm Dr. Olney’s tests. Dr. Reynolds confirmed Aspartame was, in fact, a neurotoxin in infant mice (Reynolds, 1971). Aspartame, a neurotoxin, excites the neurons to death and hence the name, excitotoxins, given this title by Dr. John Olney (Whetsell, 1993).
By March of 1973, G.D. Searle's petition for approval to market Aspartame as a sweetening agent was published in the Federal Register to the FDA. Martha M. Freeman, M.D., of the FDA Division of Metabolic and Endocrine Drug Products, addressed the credibility of the information submitted by G.D. Searle in their petition to approve Aspartame in an FDA memorandum dated September 12, 1973 (Freeman, 1973). Her complaint was that all of G.D. Searle’s studies had been single-dose studies. Dr. Freeman pointed out, as early as 1973, the inadequacy of single-dose tests of Aspartame as compared to multiple dose studies. Since then, the NutraSweet® Company has continued to published single-dose studies when most of the experimental studies to determine physical harm work in a dose-dependent fashion.
Due to the uncertainty of the regulatory future on Aspartame, construction of a large Aspartame manufacturing plant in Augusta, Georgia was halted and G.D. Searle commissioned Ajinomoto in Singapore, the inventor and main producer of the food additive monosodium glutamate, to mass-produce Aspartame in commercial quantities (Farber, 1989).
On July 26, 1974, FDA commissioner Alexander Schmidt approved the use of Aspartame in dry foods only. It was not approved for baking goods, cooking, or carbonated beverages (Farber 1989; Federal Register 1974). Despite the fact that FDA scientists found serious discrepancies in all 13 tests related to genetic and neuron damage submitted by G.D. Searle, the sweetener was approved and the agency made public, for the first time, data supporting the food-additive decision.
Following that decision, Dr. John Olney and consumer interest attorney, James Turner, author of a 1970 book about food additives, objected to the decision because Dr. Olney and his team had linked Aspartame to brain lesions in mice. Dr. Olney and James Turner filed a complaint at the FDA objecting to the approval and were able to hold it off the market until 1981. They were particularly worried about Aspartame's effects on children (Graves, 1984; Congressional Record, 1985; Federal Register, 1975; Olney, 1987).
Dr. Alexander Schmidt, in 1975, appointed a special Task Force headed by Philip Brodsky, FDA's Lead Investigator and assisted by FDA Toxicologist, Dr. Adrian Gross, to look at 25 key studies for the food additive Aspartame. All of the studies, whether conducted at G.D. Searle or Hazleton Laboratories, were under the supervision of the Pathology-Toxicology Department at G.D. Searle (Gross, 1987). FDA Toxicologist and Task Force member, Dr. Andrian Gross stated:
They [G.D. Searle] lied and they didn't submit the real nature of their observations because had they done that it is more than likely that a great number of these studies would have been rejected simply for adequacy. What Searle did, they took great pains to camouflage these shortcomings of the study. As I say filter and just present to the FDA what they wished the FDA to know and they did other terrible things for instance animals would develop tumors while they were under study. Well they would remove these tumors from the animals (Congressional Record, p. S10826-S10827).
Phillip Brodsky stated that he had never seen anything as bad as G. D. Searle's studies (Graves, 1984; Congressional Record, l985).
When G.D. Searle technicians were caught removing the brain tumors from the rats, they claimed that the rats couldn't breathe well. Dr. Adrian Gross, gave several reasons why Searle's misconduct invalidated their experiments and stated, "It is highly unlikely that the FDA investigative teams found all of the problems with G. D. Searle's studies. G. D. Searle seemed so intent on covering up their misconduct, that it is quite likely that they were able to hide many of the problems from the FDA." (Congressional Record, p. S10826-S10827) According to Dr. Russell Blaylock, no independent studies have been done to examine this vital issue. (Blaylock, 2003).
On December 5, 1975, the FDA reversed their original decision and put a hold on their approval of Aspartame due to the preliminary findings of Dr. Olney’s research as presented to the FDA Task Force. The Public Board of Inquiry was also put on hold (Federal Register, 1975; Mullarkey, 1994).
Still unable to achieve an approval status for Aspartame, G.D. Searle met with the FDA on August 4, l976 for consent to continue testing by hiring a private agency, Universities Associated for Research and Education in Pathology (UAREP). (Graves, l984; Congressional Record, l985).
G.D. Searle had invested 19.7 million dollars in an incomplete production facility and 9.2. million dollars in Aspartame inventory (Farber, 1989). Donald Rumsfeld, a former member of the U.S. Congress and the Chief of Staff during the Gerald Ford Administration, was hired as president of G.D. Searle in 1977. Attorney James Turner believes that G.D. Searle hired Rumsfeld to handle the Aspartame approval difficulties as a "legal problem rather than a scientific problem" (Gordon, 1987, p. 497 as cited in US Senate, 1987). Perhaps, G.D. Searle needed someone of political stature that could help them reap the harvest of their investments
In August 1977, the Bressler report was released. This FDA audit of studies (E5, E77/78, E89) was performed by a team of scientists led by Dr. Jerome Bressler and written by Dr. Bressler. Jerome Bressler said that G.D. Searle’s scientists’ “studies on Aspartame were so bad FDA removed 20% of the worst of his report when retyped.” Some of the flaws in the three studies found by the Bressler-led FDA Task Force included missing raw data, errors and discrepancies in available data, exclusions of animals, organ masses and enlarged and atrophied organs. An undiagnosed uterine polyp increased the incidence to 15 percent of the Aspartame-dosed animals and other multiple discrepancies (Roberts, 1990). For each of the major discrepancies found by the Task Force, the FDA Bureau of Foods minimized the problem (Gordon, 1987). Dr Jacqueline Verrett, the senior scientist of the FDA Bureau of Foods review team created to review the Bressler Report said, "It was pretty obvious that somewhere along the line, the bureau officials were working up to a whitewash" (Gordon, 1987, p. 497 as cited in US Senate, 1987). In 1987, Verrett testified before the US Senate stating that the experiments conducted by Searle were a "disaster." She stated that her team was instructed not to comment on or be concerned with the overall validity of the studies (Gold, 1995).
On September 30, 1980, the FDA Public Board of Inquiry comprised of Dr. Walle J. H. Hauta, M.D., Ph.D. Chairman; Dr. Peter W. Lampert, M.D. member; and Dr. Vernon R. Young, Ph.D. member, voted unanimously to reject the use of Aspartame until additional studies on Aspartame's potential to cause brain tumors, neurodegerative diseases and gastrointestinal diseases could be done (Brannigan 1983). The Board of Inquiry found that Aspartame becomes a deadly poison at 86 degrees Fahrenheit, Aspartame converting to formaldehyde above 86 degrees Fahrenheit, and then to formic acid, and finally to diketopiperazine (DKP), a known brain carcinogen (Martini, 1995).
In Docket No. 75P-0355, the Department of Health and Human Services of the Food and Drug Administration reported the Public Board of Inquiry’s decision on Aspartame:
On the basis of the conclusion concerning Issue Number 2, the Board concludes that approval of Aspartame for use in foods should be withheld at least until the question concerning its possible oncogenic potential has been resolved by further experiments. The Board has not been presented with proof of reasonable certainty that Aspartame is safe for use as a food additive under its intended conditions of use. The foregoing constitutes the Board's findings of fact and conclusions of law. Therefore, it is ORDERED that: 1. Approval of the food additive petition for Aspartame (FAP 3A2885) be and it is hereby withdrawn. 2. The stay of the effectiveness of the regulation for Aspartame, 21 CFR 172.804, is hereby vacated and the regulation revoked (Decision of the Public Board of Inquiry Docket No. 75P-0355, 1980, p.49).
The day after Ronald Reagan took office as U.S. President in 1981, G.D. Searle re-applied for the approval of Aspartame, submitting several new studies along with their application. It wasn’t long before President Reagan replaced Jere E. Goyan, Ph.D., who was at that time the FDA Commissioner (Gordon 1987; US Senate, 1987). Dr.Goyan was the first pharmacist to serve as Commissioner of Food and Drugs and served in that position from October 1979 to January 1981. Before Goyan was replaced by Regan appointee Dr. Arthur Hall Hayes Jr., he had set up a five-member "commissioner's team" of scientists with no prior involvement in the Aspartame issue to review the board's ruling. On May 18, 1981, one month after the appointment of Dr. Hayes, three scientists of the 5-member panel sent a letter to the panel lawyer, Joseph Levitt. Those three scientists were Satva Dubey (FDA Chief of Statistical Evaluation Branch), Douglas Park (Staff Science Advisor), and Robert Condon (Veterinary Medicine). In the letter, they made their concerns very clear about the use of Aspartame and claimed brain tumor data was so "worrisome" in one particular study that Mr. Levitt could not recommend the Aspartame be approved (Gordon 1987; US Senate, 1987, p. 495).
Searle petitioned for FDA approval again in 1982 to use the sweetener in diet soft drinks and children's vitamins, claiming that the sodas were cooler than 86 degrees (Gordon, 1987; Farber 1989) and the approval was granted. Within weeks, Dr. Arthur Hull Hayes, Jr. resigned from his position, and became a consultant to Burson-Marsteller public relations firm representing the NutraSweet Co. (Evangelista, 2004).
In 1983, despite the questions and revolving door issues, the FDA was satisfied in supporting Aspartame safety, with the exception of people with the rare disease phenylketonuria, and Aspartame was approved. However, what is becoming clear is that Aspartame is an excitotoxins and a neurotoxin (Whetsell, 1993).
Excitotoxins and the Brain
The brain, weighing only three pounds, is made up of 60 % fat, due to myelin, and has large concentrations of amino acids. These are carefully regulated because so many amino acids serve as neurotransmitters or transmitter precursors. Each amino acid performs a specific duty, and without careful control of these substances, our brains would not be able communicate properly with our bodies. Neurotransmitters are chemicals that allow the movement of information from one neuron, across the synaptic gap, to an adjacent neuron. Glutamate and aspartate, which are neurotransmitters, are electrically active and process information to be transmitted to specific neurons.
There are billions of neurons in the human brain and they all have specific jobs. Some are involved with thinking, learning, and memory. Others are responsible for receiving sensory information. Still others communicate with muscles, stimulating them into action.
Each neuron consists of a cell body, an axon, and many dendrites. The cell body contains a nucleus, which controls all of the cell's activities, and several other organelles that perform specific functions. Two types of processes extend from the cell body. The axon, which is much narrower than the width of a human hair, and transmits messages to other neurons. Messages may sometimes travel over very long distances. Dendrites receive messages from the axons of other nerve cells. Each nerve cell is connected to thousands of other nerve cells through its axon and dendrites. Additionally, neurons are surrounded by glia cells that support, protect, and nourish them. Several processes that involve communication, metabolism, and repair, all have to work smoothly together for neurons to survive and stay healthy.
In addition to being electrically active, neurons constantly synthesize neurotransmitters. Aspartate and gluamate are important neurotransmitters that allow neurons to communicate between each other. Normally, any excess aspartate and glutamate in the extrcellular fluid is pumped back in the glial cells surrounding the neurons. However, when particular types of neurons are exposed to excessive amounts of aspartate and glutamate, they are overstimulated and the cells die (Coyle, 1981).
In 1968, Dr. Olney, working out of the Department of Psychiatry at Washington University in St. Louis, repeated a study by Dr. Lucas and Newhouse, using the same animal model and the same doses of monosodium glutamate (MSG) and aspartate, one of the main ingredients in NutraSweet (Aspartame). What Dr. Olney found was that not only did MSG and aspartate cause severe damage to the neurons in the hypothalamus, but it also caused widespread destruction of neurons in other areas of the brain adjacent to the ventricular system, called the circumventricular organs (Olney, 1969).
Figure 2. Circumventricular Organs of the Brain. These areas lack a blood-brain barrier. . Illustration by Dr.Russell L. Blaylock.
Because the hypothalamus plays such an important role in controlling so many functions, this discovery by Dr. Olney is particularly important. Since the FDA approved Aspartame, the mounting evidence of this type of destruction to neurons by aspartate is being demonstrated in over 92 symptoms, including death, registered at the FDA. (Department of Health and Human Services, 1995).
The wiring of the hypothalamus is some of the most complex in the nervous system, with vital connections to the pituitary gland, the limbic system, the hippocampus, the striatum and the brain stem. The pituitary, the master gland, is only about the size of a white navy bean, and yet it is responsible for controlling some of the most vital hormonal systems in the body, including those of the endocrine glands. It also controls the adrenals, the thyroid, and the reproductive organs by releasing small amounts of its controlling hormones into the blood stream, sending messages to other endocrine organs to regulate secretion of their hormones. The hypothalamus, no larger than a fingernail, works with the body’s pituitary gland to help regulate emotions, autonomic control, parasympathetic and sympathetic responses, hunger satiety, immunity, memory input, and anger control. If these vital brain functions experience any disruption, it can result in anything from minor behavioral problems or endocrine malfunctions to major disruptions in sexual function, obesity, immune suppression, and endocrine gland failure.
It is now known that the hypothalamus is associated with neurological diseases caused by injuries or assaults that create lesions by the di-peptide of phenylalanine and aspartate, known as Aspartame (Blaylock, 2000). Among the many neurons in the hypothalamus, called nuclei, the arcuate or curved nucleus is consistently the most sensitive to Aspartame toxicity. This nucleus regulates growth hormone secretions with the help of the pituitary, and with its association with other nuclei, such as the supraoptic nucleus and paraventricular nucleus. It has been demonstrated many times in laboratory studies that these excitotoxins cause shrinkage of the pituitary, thyroid, adrenals and gonads in animals exposed to high concentrations of Aspartame (Blaylock, 2000).
The hypothalamus is one of the areas of the brain that is not protected by the blood-brain barrier and extremely fragile to excitotoxins. Aspartate is a major neurotransmitter in the hypothalamus and therefore excess concentrations of it will affect all of the various nuclei in the hypothalamus.
In order to understand this destructive process, it is important to understand how excitatory amino acids were discovered and how they cause the neurons to fire spontaneously and repeatedly. In the early part of 1950, Dr. T. Hayaski, a neuroscientist, was experimenting on a dog by injecting monosodium glutamate into the gray matter of a dog’s brain. The dog collapsed in its cage and immediately began to convulse. Dr. T. Hayaski concluded that the glutamate was triggering the dog’s brain cells to become overexcited and fire uncontrollably (Blaylock, 1997). In 1959, in a different lab, two other researchers, Dr. A. Van Harreveld and Dr. M. Mendelson placed glutamate and aspartate on the muscle tissue of invertebrate crustaceans and they noted that the muscle tissue contracted violently (Van Harreveld & Medelson, 1959). They recognized these amino acids as being part of a new functional category of molecules and gave them the name of "excitatory amino acids" because they caused nerve cells to become excited (Blaylock, 1997). Since then, over seventy excitatory aminos acids have been discovered. It was not until 1973 that these excitotoxins would be demonstrated to be neurotransmitters.
Neurons communicate with each other across a tiny fissure known as the synaptic cleft. The electrical impulse is carried from the axon terminal of the pre-synaptic cell to the receptors on the dendrites of the postsynaptic cell. However, they never physically touch one another.
Figure 3. When a nerve impulse passes the axon terminal, its synaptic vesicles release their stored chemicals into the synaptic cleft. These diffuse through the cleft to reach the membrane of the next neuron, stimulating the latter. This causes the nerve impulse to be transmitted to the next neuron.
Neurotransmitters are endogenous chemicals and are manufactured in the neuron’s cell body. The transmission of information from one neuron to another depends on the ability of the information to traverse the synapse between the terminal end of one neuron and the receptor end of an adjacent neuron. The transfer is accomplished by neurotransmitters. The neurotransmitter molecule attaches to a receptor on the membrane of the dendrite and causes the molecule in the membrane to change. This is likened to a lock and key system. The receptor on the membrane is the lock and the neurotransmitter is the key. As you know, not any key can open any lock. It must be a specific key that will fit perfectly. When this happens, it opens a microscopic channel within the membrane and lets sodium and/or calcium spew inside the axon, which in turn triggers the cell to fire a transmitting signal down its axon fiber.
Figure 4. Neurotransmitters crossing the synaptic cleft. Illustration from Bipolar Disorders: A Guide to Helping Children by Mitzi Waltz.
It is now well known that two of the most common neurotransmitting chemicals, glutamate and aspartate, found normally in the brain and spinal cord, will become neurotoxic to the neurons containing glutamate receptors and to the nerves connected to these neurons when their concentrations rise above a critical level (Blaylock, 1999). This means that not only will the neurotoxic levels kill the selected neurons, but also kill any neurons that happen to be connected to it, even if that neuron uses another type of receptor. For this reason, the nervous system keeps a tight control on the concentration of these two amino acids in the extracellular space. This is done by a system designed to remove any excess glutamate from this surrounding fluid. A special pump system is set in place to transfer the excess glutamate back into surrounding glial cells that supply the neurons with energy. If this pump fails, the destruction is inevitable.
This pump system requires an immense amount of cellular energy that is supplied by an energy carrier known as adenosine triphosphate (ATP). ATP is a molecule that is the immediate source of energy for all cellular activity, including muscle contraction. It is an organic compound composed of adenine, ribose, and three phosphate groups. This is a very unstable molecule primarily because the phosphate groups contain negative electrical charges that repel each other. However, when the phosphate groups break free, energy is released. This tri-molecule is the spark plug that transports chemical energy within cells for metabolism, and is also involved in the activation of amino acids, a necessary step in the synthesis of protein. When ATP loses one of its phosphate groups, and this happens after the process of hydrolysis instigated by the enzyme ATPase, it is brought down to a di-molecule called, adenosine diphosphate (ADP). The muscle contraction is powered by the breakdown of these two molecules, ATP and ADP. If the ADP loses a phosphate and becomes adenosine monophosphate (AMP) and runs out of energy, then once again, destruction is inevitable. Eventually, through a donation of phosphate from creatine, ATP will be restored.
This glutamate pumping system is likened to a boat in the water with a boat crew on broad. If the boat springs a leak, then the boat crew becomes the bucket brigade, scooping up water as it is filling up the sinking boat. If the crew is tired and runs out of energy, the boat will fill up with water and sink. The same thing happens when energy production is reduced in the brain. If the ATP is not restored to the neurons, as mentioned in the previous paragraph, then they will die or be excited to death, thus, the term, excitotoxins. Excitotoxins are biochemical substances, usually amino acids, amino acid analogs, or amino acid derivatives, that can react with specialized neuronal receptors, such as glutamate receptors, in the brain or spinal cord in such a way as to cause injury or death to a wide variety of neurons
Studies have shown within fifteen to thirty minutes of highly concentrated dosages of excitotoxins (MSG, glutamate, Aspartame), suspended in tissue culture, the degeneration of the organelles within the cell and clumping of the chromatin in the nucleus is visible under a microscope. Within three hours, not only have the neurons died, but the body’s defense mechanism has begun the process of hauling away debris. This in turn puts enormous stress on the body’s systems (Choi, 1990).
Figure 5. When a neuron is exposed to a massive dose of an excitotoxin, the cell immediately begins to swell and dies within one hour. Within two hours, the macrophages begin to clear the remains. When a lower dose is administered, nothing happens until the second hour. This delayed death of the neurons is characteristic of excitotoxins. Illustration by Dr.Russell L. Blaylock.
However, with exposure to lower doses of excitotoxins, neurons during the first 15 to 30 minutes appear to be perfectly normal and unharmed. It is not until the second hour when the cells begin to commit apoptosis. Figure 5 represents the progression over the course of two hours from the start of exposure (Coyle, 1981).
What these studies demonstrate is that two different reactions create cellular destruction: acute and delayed. The acute reaction that happened within the first hour mimicked the result of a massive influx of sodium to the inside of the neuron. Having a rapid movement of sodium into the cell causes it to swell due to osmotic movement of water into the cell; as it swells out, it bursts and dies. Sodium enters the cell by a selective channel or pore that is controlled by special triggering chemicals. Exogenous glutamate isolates acts as a trigger to open the sodium channel on the cell’s membrane. No matter what concentration of excitotoxins was added to a culture of sensitive neurons, the cells would die during the critical two-hour period (Rothman, 1985; Lucas & Newhouse 1957).
There was no effect on the delayed reaction when removing the sodium. After two hours the neurons still died. At the time, the scientists were considering another channel that might explain the delayed reaction. The study was repeated and that time the scientists removed calcium from the tissue medium. They waited the allotted two hours with no cellular death, then 24 hours and still no cellular death. Calcium appeared to be implicated in the delayed response. Putting it all together, they realized that glutamate opens a special channel designed to allow calcium to enter the neuron, and it was calcium that triggered the cell to die (Blaylock, 1997).
Neurons contain calcium channels that regulate the movement of calcium into the cell. These are important to creating a normal environment inside each neuron and playing a vital role in the activation of neurons and the transmission of their impulses. The calcium channel, once it has been stimulated, will open for no more than a fraction of a second, and only then are minute amounts of calcium allowed to enter the neuron. There is a special protective pump set in place in case too much calcium enters the neuron. This special calcium pump drives the excess calcium back out of the neuron; some of the calcium is also captured and stored within the endoplasmic reticulum of the cell.
Asparate and all excitotoxins appear to work by opening the calcium channels of specific receptors. When these neurotransmitters are allowed to come into contact with the receptor in too high a concentration or for too long a period of time, the calcium channel is forced to stay open (Blaylock, 2000). As the calcium pours into the cell, the cell will explode and die. Just like the bucket brigade uses up its ATP when the boat is beginning to fill up and sink, so too is the calcium pump in dire need of ATP for energy to help siphon out all the excess calcium (Blaylock, 1997).
When dealing with glutamate receptors, it gets a bit complicated. Glutamate is the key and the glutamate receptor on the membrane is the lock, but it is now believed that there are more than twenty sub-types of glutamate receptors on the cell membrane (Watkin & Evans, 1981). It was discovered that a substance that was being used by scientists, called N-methyl-D-aspartate or NMDA, a glutamate analogue, stimulates only certain classes of glutamate receptor and not others. Another substance, called quisqualate, was found to stimulate a completely different set of glutamate receptors, and then a third receptor sub-type was found that responds only to the chemical kainite. All three sub-types of glutamate receptors on the nerve cell membranes can be stimulated with glutamate and/or aspartate (Monaghan, Bridges & Cotman, 1989). NMDA acts as the gatekeeper of the calcium channel on the cell membrane and regulates the entry of calcium into the neuron (Watkins & Evans, 1981). Both glutamate and aspartate can open this calcium channel. Therefore, unlike other lock and key neurons and neurotransmitters, with the NMDA receptor more than one key is required.
The zinc receptor, magnesium receptor, and glycine receptor are the other locks on the membrane. Zinc locks the door and closes the calcium channel tight. Magnesium also locks the door, but there is a notable difference between the two. When zinc locks the door on the calcium channel, it remains bound even if the neuron has been fired, whereas when magnesium locks the calcium channel, it is automatically released when the neuron fires. Glycine is another amino acid necessary for the calcium channel to open. Scientists found that when glycine is removed from a culture of nerve cells, no concentration of glutamate would make the nerve cell fire. However, when glycine is added to a culture of nerve cells, the neurons become much more sensitive to the excitotoxins and, if they are not protected or rescued, they will eventually be destroyed (Choi, 1989).
Once glutamate or aspartate come into contact with the receptor, they slide into the lock, the glutamate receptor, like a perfect fitting key. Then glycine is inserted into its lock close by. When normal levels of magnesium and low levels of zinc are present near the neurons, the channel will then open wide, and calcium and sodium will pour into the neurons, causing it to fire (Kleckner & Dingledine, 1988).
During the opening of the calcium channel in NMDA and glutamate receptors, the excess intracellular calcium also activates nitric oxide synthase (NOS), which generates excessive amounts of nitric oxide (NO). The NO then reacts with superoxide to form peroxynitrite radical, which is a very powerful reactive nitrogen species (RNS). This RNS passes through the mitochondrial membrane with great speed and has been shown to be especially damaging to mitochondrial enzymes and mitochondrial DNA (mtDNA) (Christopherson & Bredt, 1997).
Neurons communicate with other neurons. The nervous system functions by passing information from neuron to neuron. This neuron-to-neuron communication has a language and it is made up of various chemicals that are specific chemicals used to send out special messages around the inside of the cell.
As calcium enters the cell, it activates a mediator called protein kinase C. This enzyme mediates the phosphorylation of certain cellular proteins and is in charge of such important functions as cell growth, ion channel activity, secretion, and the mechanisms by which a presynaptic neuron influences the activity of a nearby postsynaptic neuron, known as a synaptic transmission. Protein kinase C causes more calcium to be released from a special calcium storage site within the cell, called the endoplasmic reticulum. Because of this, more calcium pours into the cytoplasm and, at times, can alter the membrane of the cell causing the calcium channel to be inactivated. When this happens, calcium continues to pour into the cytoplasm of the cells, which in turn, sends signals to another enzyme called, phospholipase C. This enzyme is responsible for breaking down some of the fatty acids within the plasma phospholipid membrane and compartmental membranes. Excess calcium within the cell is also destructive to the cell's mitochondria, structures that are involved in the cell's abiltliy to produce ATP. Mitochondria soak up excess calcium until they swell up and stop functioning. If enough mitochondria are damaged, nerve cells degenerates (Nairn, Hemmings, & Greengard, 1985).
In the process of breaking down this phospholipid membrane, arachidonic acid is released. Once in the interior of the cell, arachidonic acid can cause great harm to the cell, especially if it is in high concentration (Farooqui & Horrocks, 1998)
As arachidonic acid is released in the interior of the cell, it becomes a target for two other enzymes, lipoxygenase and cyclooxygenase (COX). These two enzymes start digesting the arachidonic acid and thus the destruction begins. A series of reactions takes place that produces a number of chemicals that trigger prostaglandin synthesis, thus creating free radical formation and rapid cell death. This cascade of destruction starts because of a deregulation of calcium, instigating the cell to swell and explode. A by-product of this reaction is the creation of free radicals (Blaylock, 1997).
In order to understand the extent of damage that takes place within the neuron when this cascade of destruction occurs, it is important to understand what a free radical is. Atoms are most stable in the ground state (the state of least possible energy in a physical system). An atom is considered "grounded" when every electron in its outermost shell has a complementary electron that spins in the opposite direction. By definition, a free radical is any atom with at least one unpaired electron in its outermost shell, that is capable of independent existence. A free radical is easily formed when a covalent bond between atoms is broken and one electron remains with each newly formed atom. Free radicals play a central role in almost every injury and disease known to man, from cancer to neurodegenerative diseases (Stadtman, 1992).
Free radicals are not only produced during disease or injury, but also are inadvertently produced when energy is utilized in the cells during metabolism. Free radicals involving oxygen are referred to as reactive oxygen species (ROS). Some oxygen molecules that have become free radicals are unstable, highly reactive, and react with the plasma phospholipid and organelle membranes, weakening the structure of the cell and disrupting the cell’s function. Once these free radicals are released, they react indiscriminately with many molecules destroying everything, even the genes (Packer & Colman, 1999). Each of our cells suffers over 10,000 hits per day from free radical molecules (Cherniske, 2003).
Figure 6. Shows how calcium activates destruction reaction from within the neuron by triggering prostaglandin synthesis and free radical formation. Illustration by Dr. Russell L. Blaylock, M.D.
Not all neurons die because of excitotoxins. Excitotoxins are very selective in attaching themselves to specific neurons. Their targeting is based on specific receptors on some neurons for glutamate and not others. Almost all excitotoxins, such as aspartate, attach themselves to the glutamate receptors on the membranes and stimulate the neurons (Choi, 1988).
As a neurotransmitter, glutamate is found in about 50% of the forebrain synapses of all mammalian brains. The fact that these receptors are concentrated in specific brain areas that are affected by Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis (ALS), suggests that these excitotoxins play a role in these diseases (Maragos, 1987; Spencer, 1987; Plaitakis, 1990).
A broad range of chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis (MS), and dementia are now believed to be caused by the excitotoxic action of glutamate and aspartate. What is true about the characteristics of all these neurodegenerative diseases is that they all develop in normal brains and slowly progress into death. Each disease appears to have a specialized group of cells that are affected by excitotoxins.
It was first believed that these specific neurons lived a shorter life than normal neurons, and that their accelerated aging process was built into their genetic coding. W.R. Gowers, a famous neurologist at the turn of the century, first popularized this theory calling the process "abiotrophy." However, as science evolved, so did our understanding of how and when neuron death occurs. It is understood today that as the neurons are being destroyed and meeting their deaths because of excitoxins or genetic factors, the symptoms do not appear until much later in life. As scientists observe in Parkinson’s disease or Alzheimer’s disease, the symptoms do not manifest themselves until over 80 to 90% of the specific neurons have died (Calne, Michael & Zigmond, 1991). These neurons did not just die all at once. Dr. Russell Blaylock refers to this degrading process as the "Creeping Death."
Why does this happen to certain neurons and not to others? Some scientists believe that these specific neurons begin to slowly die due to an autoimmune condition wherein the immune system begins by attacking the nervous system. However, the results of extensive studies to make that connection to the neurodegenerative diseases are not that convincing (Blaylock, 1997). The most plausible connection, that makes scientific sense, outside of genetics, is that toxins in the environment are causing neurodegenerative diseases (Kurland, 1988).
From 1940 to 1980, epidemiologists studied the Chamorros Indians, natives of the Mariana Islands in Guam that were dying from a mysterious disease. The natives began to waste away and became too weak to stand or even swallow their food. Eventually, the doctors realized that this disorder resembled ALS. What brought them to the hypothesis that these diseases would have an environmental connection was the fact that these native Indians had fifty to hundred times higher incidents of ALS than developed countries, suggesting clear that something was attacking them from their own environment (Kurland, 1988).
What was affecting them was a neurotoxin found within the food they were consuming. The natives ate a large amount of a plant called cycas circinalis, or cycad, from the false sago palm. Cycad has a toxic compound called β -N-methylamino-L-alanine (L-BMAA) which has been found to cause seizures in mice. One researcher, Dr. George Spencer, found another toxic compound, called β-oxalylamino-L-alanine (L-BOAA), that caused sudden onset of weakness and paralysis in the legs. While continuing to research, Dr. Spencer came across a report about a single monkey fed a concentrated solution of L-BMAA for several weeks (Kurland, 1988). The monkey developed the same disease the natives were dying of in Guam. When Dr. Spencer necropsied the monkey, he found that it had the identical pathological changes in its spinal cord and brain as did the natives. Dr. Spencer repeated the same experiment again, only this time on thirteen monkeys. After two to twelve weeks of consuming a concentrated solution of L-BMAA, the same monkeys exhibited signs of ALS and Parkinson’s disease. They developed signs of severe weakness in their limbs, a shuffling gait, and a blank stare with a mask-like expression on their face (Spencer, Nunn & Hugon, 1987).
Everyone has a different sensitivity to toxins. Some respond immediately, others experience no symptoms at all until it is too late, and some remain resistant to certain toxins with no side effects. Resistance can depend on the protective mechanisms within a person’s blood brain barrier (BBB), the ionic and glutamate pumps, and the free radical scavengers. Many immigrants from Guam migrated to the United States and while they appeared to be normal, within the following thirty years they developed ALS. The question is did those toxins reside quietly in their neurons and become active in killing the same neurons in their spinal cord decades later?
It is possible that the natives migrated from the island where they were consuming massive amounts of food with high levels of neurotoxins, the level of exposure to these neurotoxins was only up to 50% of target cell deaths – below the threshold for neurological symptoms. Degenerative neurological diseases do not appear until 80% to 90% of the specific cells in the brain are dead. Once 80% to 90% of the central nervous system (CVS) motor neurons are completely killed, then all the signs of these neurodegenerative diseases will appear. It is obvious, this kind of destruction does not happen overnight. Once these immigrants were in the United States, it is possible that they began to consume American foods and drinks that are high in monosodium glutamate, drink sodas with Aspartame and use NutraSweet® in their coffee. With the addition of these neurotoxins added to their diet, the 50% levels within their brains rose to beyond 80% to 90%. At this stage, many developed ALS, ten to fifteen times the United States rate (Blaylock, 1997).
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