(c) 1999
by Russell L. Blaylock, M.D.
There are a growing number of clinicians and basic scientists who areconvinced that excitotoxins play a critical role in the development ofseveral neurological disorders, including migraines, seizures,infections, abnormal neural development, certain endocrine disorders,specific types of obesity, and especially the neurodegenerativediseases; a group of diseases which includes: ALS, Parkinson’s disease,Alzheimer’s disease, Huntington’s disease, and olivopontocerebellardegeneration.
An enormous amount of both clinical and experimental evidence hasaccumulated over the past decade supporting this basic premise. Yet, theFDA still refuses to recognize the immediate and long term danger to thepublic caused by the practice of allowing various excitotoxins to beadded to the food supply, such as MSG, hydrolyzed vegetable protein, andaspartame. The amount of these neurotoxins added to our food hasincreased enormously since their first introduction. For example, since1948 the amount of MSG added to foods has doubled every decade. By 1972262,000 metric tons were being added to foods. Over 800 million poundsof aspartame have been consumed in various products since it was firstapproved. Ironically, these food additives have nothing to do withpreserving food or protecting its integrity. They are all used to alterthe taste of food. MSG, hydrolyzed vegetable protein, and naturalflavoring are used to enhance the taste of food so that it taste better.Aspartame is an artificial sweetener.
The public must be made aware that these toxins ( excitotoxins) arenot present in just a few foods but rather in almost all processedfoods. In many cases they are being added in disguised forms, such asnatural flavoring, spices, yeast extract, textured protein, soy proteinextract, etc. Experimentally, we know that when subtoxic ( below toxiclevels) of excitotoxins are given to animals, they experience fulltoxicity. Also, liquid forms of excitotoxins, as occurs in soups,gravies and diet soft drinks are more toxic than that added to solidfoods. This is because they are more rapidly absorbed and reach higherblood levels.
So, what is an excitotoxin? These are substances, usually aminoacids, that react with specialized receptors in the brain in such a wayas to lead to destruction of certain types of brain cells. Glutamate isone of the more commonly known excitotoxins. MSG is the sodium salt ofglutamate. This amino acid is a normal neurotransmitter in the brain. Infact, it is the most commonly used neurotransmitter by the brain.Defenders of MSG and aspartame use, usually say: How could a substancethat is used normally by the brain cause harm? This is because,glutamate, as a neurotransmitter, is used by the brain only in very ,very small concentrations – no more than 8 to 12ug. When theconcentration of this transmitter rises above this level the neuronsbegin to fire abnormally. At higher concentrations, the cells undergo aspecialized process of cell death.
The brain has several elaborate mechanisms to prevent accumulation ofMSG in the brain. First is the blood-brain barrier, a system thatimpedes glutamate entry into the area of the brain cells. But, thissystem was intended to protect the brain against occasional elevation ofglutamate of a moderate degree, as would be found with un-processed foodconsumption. It was not designed to eliminate very high concentrationsof glutamate and aspartate consumed daily, several times a day, as wesee in modern society. Several experiments have demonstrated that undersuch conditions, glutamate can by-pass this barrier system and enter thebrain in toxic concentrations. In fact, there is some evidence that itmay actually be concentrated within the brain with prolonged exposures.
There are also several conditions under which the blood-brain barrier( BBB) is made incompetent. Before birth, the BBB is incompetent andwill allow glutamate to enter the brain. It may be that for aconsiderable period after birth the barrier may also incompletelydeveloped as well. Hypertension, diabetes, head trauma, brain tumors,strokes, certain drugs, Alzheimer’s disease, vitamin and mineraldeficiencies, severe hypoglycemia, heat stroke, electromagneticradiation, ionizing radiation, multiple sclerosis, and certaininfections can all cause the barrier to fail. In fact, as we age thebarrier system becomes more porous, allowing excitotoxins in the bloodto enter the brain. So there are numerous instances under whichexcitotoxin food additives can enter and damage the brain. Finally,recent experiments have shown that glutamate and aspartate( as in aspartame) can open the barrier itself.
Another system used to protect the brain against environmentalexcitotoxins, is a system within the brain that binds the glutamatemolecule ( called the glutamate transporter) and transports it to aspecial storage cell ( the astrocyte) within a fraction of a secondafter it is used as a neurotransmitter. This system can be overwhelmedby high intakes of MSG, aspartame and other food excitotoxins. It isalso known that excitotoxins themselves can cause the generation ofnumerous amounts of free radicals and that during the process of lipidperoxidation ( oxidation of membrane fats) a substance is producedcalled 4-hydroxynonenal. This chemical inhibits the glutamatetransporter, thus allowing glutamate to accumulate in the brain.
Excitotoxins destroy neurons partly by stimulating the generation oflarge numbers of free radicals. Recently, it has been shown that thisoccurs not only within the brain, but also within other tissues andorgans as well ( liver and red blood cells). This could, from allavailable evidence, increase all sorts of degenerative diseases such asarthritis, coronary heart disease, and atherosclerosis,as well as inducecancer formation. Certainly, we would not want to do something thatwould significantly increase free radical production in the body. It isknown that all of the neurodegenerative disease, such as Parkinson’sdisease, Alzheimer’s disease, and ALS, are associated with free radicalinjury of the nervous system.
It should also be appreciated that the effects of excitotoxin foodadditives generally is not dramatic. Some individuals may be especiallysensitive and develop severe symptoms and even sudden death from cardiacirritability, but in most instances the effects are subtle and developover a long period of time. While MSG and aspartame are probably notcauses of the neurodegenerative diseases, such as Alzheimer’s dementia,Parkinson’s disease, or amyotrophic lateral sclerosis, they may wellprecipitate these disorders and certainly worsen their effects. It maybe that many people with a propensity for developing one of thesediseases would never develop a full blown disorder had it not been fortheir exposure to high levels of food borne excitotoxin additives. Somemay have had a very mild form of the disease had it not been for theexposure.
In July, 1995 the Federation of American Societies for ExperimentalBiology ( FASEB) conducted a definitive study for the FDA on thequestion of safety of MSG. The FDA wrote a very deceptive summery of thereport in which they implied that, except possibly for asthma patients,MSG was found to be safe by the FASEB reviewers. But, in fact, that isnot what the report said at all. I summarized, in detail, my criticismof this widely reported FDA deception in the revised paperback editionof my book, Excitotoxins: The Taste That Kills, by analyzing exactlywhat the report said, and failed to say. For example, it never said thatMSG did not aggravate neurodegenerative diseases. What they said was,there were no studies indicating such a link. Specifically, that no onehas conducted any studies, positive or negative, to see if there is alink. In other words it has not been looked at. A vital difference.
Unfortunately, for the consumer, the corporate food processors notonly continue to add MSG to our foods but they have gone to great linksto disguise these harmful additives. For example, they use such names ahydrolyzed vegetable protein, vegetable protein, hydrolyzed plantprotein, caseinate, yeast extract, and natural flavoring. We knowexperimentally, as stated, when these excitotoxin taste enhancers areadded together they become much more toxic. In fact, excitotoxins insubtoxic concentrations can be fully toxic to specialized brain cellswhen used in combination. Frequently, I see processed foods onsupermarket shelves, especially frozen of diet food, that contain two,three or even four types of excitotoxins. We also know that excitotoxinsin a liquid form are much more toxic than solid forms because they arerapidly absorbed and attain high concentration in the blood. This meansthat many of the commercial soups, sauces, and gravies containing MSGare very dangerous to nervous system health, and should especially beavoided by those either having one of the above mentioned disorders, orare at a high risk of developing one of them. They should also beavoided by cancer patients and those at high risk for cancer.
In the case of ALS, amyotrophic lateral sclerosis, we know thatconsumption of red meats and especially MSG itself, can significantlyelevate blood glutamate, much higher than is seen in the normalpopulation. Similar studies, as far as I am aware, have not beenconducted in patients with Alzheimer’s disease or Parkinson’s disease.But, as a general rule I would certainly suggest that person’s witheither of these diseases avoid MSG containing foods as well as redmeats, cheeses, and pureed tomatoes, all of which are known to have highlevels of glutamate.
It must be remembered that it is the glutamate molecule that is toxicin MSG ( monosodium glutamate). Glutamate is a naturally occurring aminoacid found in varying concentrations in many foods. Defenders of MSGsafety allude to this fact in their defense. But, it is free glutamatethat is the culprit. Bound glutamate, found naturally in foods, is lessdangerous because it is slowly broken down and absorbed by the gut, sothat it can be utilized by the tissues, especially muscle, before toxicconcentrations can build up. Therefore, a whole tomato is safer than apureed tomato. The only exception to this, based on present knowledge,is in the case of ALS. Also, in the case of tomatoes, the plant containsseveral powerful antioxidants known to block glutamate toxicity.
Hydrolyzed vegetable protein should not be confused with hydrolyzedvegetable oil. The oil does not contain appreciable concentration ofglutamate, it is an oil. Hydrolyzed vegetable protein is made by achemical process that breaks down the vegetable’s protein structure topurposefully free the glutamate, as well as aspartate, anotherexcitotoxin. This brown powdery substance is used to enhance the flavorof foods, especially meat dishes, soups, and sauces. Despite the factthat some health food manufacturers have attempted to sell the idea thatthis flavor enhancer is ‘ all natural’ and ‘safe’ because it is madefrom vegetables, it is not. It is the same substance added to processedfoods. Experimentally, one can produce the same brain lesions usinghydrolyzed vegetable protein as by using MSG or aspartate.
A growing list of excitotoxins is being discovered, including severalthat are found naturally. For example, L- cysteine is a very powerfulexcitotoxin. Recently, it has been added to certain bread dough and issold in health food stores as a supplement. Homocysteine, a metabolicderivative, is also an excitotoxin. Interestingly, elevated blood levelsof homocysteine has recently been shown to be a major, if not the major,indicator of cardiovascular disease and stroke. Equally interesting, isthe finding that elevated levels have also been implicated inneurodevelopmental disorders, especially anencephaly and spinaldysraphism ( neural tube defects). It is thought that this is theprotective mechanism of action of the prenatal vitamins B12, B6, andfolate when used in combination. It remains to be seen if the toxiceffect 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 allAlzheimer’s patients examined had elevated levels of homocysteine.
Recent studies have shown that persons affected by Alzheimer’sdisease also have widespread destruction of their retinal ganglioncells. Interestingly, this is the area found to be affected when Lucasand Newhouse first discovered the excitotoxicity of MSG. While this doesnot prove that dietary glutamate and other excitotoxins cause oraggravate Alzheimer’s disease, it makes one very suspicious. One couldargue a common intrinsic etiology for central nervous system neuronaldamage and retinal ganglion cell damage, but these findings aredisconcerting enough to warrant further investigations.
The Free Radical Connection
It is interesting to note that many of the same neurological diseasesassociated with excitotoxic injury are also associated withaccumulations of toxic free radicals and destructive lipid enzymes. Forexample, the brains of Alzheimer’s disease patients have been found tocontain high concentration of lipolytic enzymes, which seems to indicateaccelerated membrane lipid peroxidation, again caused by free radicalgeneration.
In the case of Parkinson’s disease, we know that one of the earlychanges is the loss of glutathione from the neurons of the striatesystem, especially in a nucleus called the substantia nigra. It is thisnucleus that is primarily affected in this disorder. Accompanying this,is an accumulation of free iron, which is one of the most powerful freeradical generators known. One of the highest concentrations of iron inthe body is within the globus pallidus and the substantia nigra. Theneurons within the latter are especially vulnerable to oxidant stressbecause the oxidant metabolism of the transmitter-dopamine- can proceedto the creation of very powerful free radicals. That is, it can auto-oxidize to peroxide,which is normally detoxified by glutathione. As wehave seen, glutathione loss in the substantia nigra is one of theearliest deficiencies seen in Parkinson’s disease. In the presence ofhigh concentrations of free iron, the peroxide is converted into thedangerous, and very powerful free radical, hydroxide. As the hydroxideradical diffuses throughout the cell, destruction of the lipidcomponents of the cell takes place, a process called lipid peroxidation.
Using a laser microprobe mass analyzer, researchers have recentlydiscovered that iron accumulation in Parkinson’s disease is primarilylocalized in the neuromelanin granules ( which gives the nucleus itsblack color). It has also been shown that there is dramatic accumulationof aluminum within these granules. Most likely, the aluminum displacesthe bound iron, releasing highly reactive free iron. It is known thateven low concentrations of aluminum salts can enhance iron-induced lipidperoxidation by almost an order of magnitude. Further, direct infusionof iron into the substantia nigra nucleus in rodents can induce aParkinsonian syndrome, and a dose related decline in dopamine. Recentstudies indicate that individuals having Parkinson’s disease also havedefective iron metabolism.
Another early finding in Parkinson’s disease is the reduction incomplex I enzymes within the mitochondria of this nucleus. It is wellknown that the complex I enzymes are particularly sensitive to freeradical injury. These enzymes are critical to the production of cellularenergy. When cellular energy is decreased, the toxic effect ofexcitatory amino acids increases dramatically, by as much as 200 fold.In fact, when energy production is very low, even normal concentrationsof extracellular glutamate and aspartate can kill neurons.
One of the terribly debilitating effects of Parkinson’s disease is acondition called ‘ freezing up’, a state where the muscle are literallyfrozen in place. There is recent evidence that this effect is due to theunopposed firing of a special nucleus in the brain ( the subthalamicnucleus). Interestingly, this nucleus uses glutamate for itstransmitter. Neuroscientist are exploring the use of glutamate blockingdrugs to prevent this disorder.
And finally, there is growing evidence that similar free radicaldamage, most likely triggered by toxic concentrations of excitotoxins,causes ALS. Several studies have demonstrated lipid peroxidation productaccumulation within the spinal cords of ALS victims. Iron accumulationhas also been seen in the spinal cords of ALS victims.
Besides the well known reactive oxygen species, such as super oxide,hydroxyl ion, hydrogen peroxide, and singlet oxygen, there exist a wholespectrum of reactive nitrogen species derived from nitric oxide, themost important of which is peroxynitrate. These free radicals can attackproteins, membrane lipids and DNA, both nuclear and mitochondrial, whichmakes these radicals very dangerous.
It is now known that glutamate acts on its receptor via a nitricoxide mechanism.Overstimulation of the glutamate receptor can result inaccumulation of reactive nitrogen species, resulting in theconcentration of several species of dangerous free radicals. There isgrowing evidence that, at least in part, this is how excess glutamatedamages nerve cells. In a multitude of studies, a close link has beendemonstrated between excitotoxity and free radical generation. Othershave shown that certain free radical scavengers ( anti-oxidants), havesuccessfully blocked excitotoxic destruction of neurons. For example,vitamin E is known to completely block glutamate toxicity in vitro ( inculture). Whether it will be as efficient in vivo ( in a living animal)is not known. But, it is interesting in light of the recentobservations that vitamin E slows the course of Alzheimer’s disease, ashad already been demonstrated in the case of Parkinson’s disease. Thereis some clinical evidence, including my own observations, that vitamin Ealso slows the course of ALS as well, especially in the form of D-Alpha-tocopherol. I would caution that anti-oxidants work best incombination and when use separately can have opposite, harmful, effects.That is, when antioxidants, such as ascorbic acid and alpha tocopherol,become oxidized themselves, such as in the case of dehydroascorbic acid,they no longer protect, but rather act as free radicals themselves. Thesame is true of alpha-tocopherol.
We know that there are four main endogenous sources of oxidants:
1. Those produced naturally from aerobic metabolism of glucose.
2. Those produced during phagocytic cell attack on bacteria, viruses,
and parasites, especially with chronic infections.
3. Those produced during the degradation of fatty acids and other
molecules that produce H2O2 as a by-product. ( This is important in
stress, which has been shown to significantly increase brain levels of
free radicals.) And
4. Oxidants produced during the course of p450 degradation of natural
toxins.
And, as we have seen, one of the major endogenous sources of freeradicals is from exposure to free iron. Unfortunately, iron is onemineral heavily promoted by the health industry, and is frequently addedto many foods, especially breads and pastas. Copper is also a powerfulfree radical generator and has been shown to be elevated within thesubstantia nigra nucleus of Parkinsonian brains.
When free radicals are generated, the first site of damage is to thecell membranes, since they are composed of polyunsaturated fatty acidmolecules known to be highly susceptible to such attack. The process ofmembrane lipid oxidation is known as lipid peroxidation and is usuallyinitiated by the hydroxal radical. We know that one’s diet cansignificantly alter this susceptibility. For example, diets high inomega 3-polyunsaturated fatty acids ( fish oils and flax seed oils) canincrease the risk of lipid peroxidation experimentally. Contrawise,diets high in olive oil, a monounsaturtated oil, significantly lowerslipid peroxidation risk. From the available research.The beneficialeffects of omega 3-fatty acid oils in the case of strokes and heartattacks probably arises from the anticoagulant effect of these oils andpossibly the inhibition of release of arachidonic acid from the cellmembrane. But, olive oil has the same antithrombosis effect andanticancer effect but also significantly lowers lipid peroxidation.
The Blood-Brain Barrier
One of the MSG industry’s chief arguments for the safety of theirproduct is that glutamate in the blood cannot enter the brain because ofthe blood-brain barrier ( BBB), a system of specialized capillarystructures designed to exclude toxic substance from entering the brain.There are several criticisms of their defense. For example, it is knownthat the brain, even in the adult, has several areas that normally donot have a barrier system, called the circumventricular organs. Theseinclude the hypothalamus, the subfornical organ, organium vasculosum,area postrema, pineal gland, and the subcommisural organ. Of these, themost important is the hypothalamus, since it is the controlling centerfor all neuroendocrine regulation, sleep wake cycles, emotional control,caloric intake regulation, immune system regulation and regulation ofthe autonomic nervous system. Interestingly, it has recently been foundthat glutamate is the most important neurotransmitter in thehypothalamus. Therefore, careful regulation of blood levels of glutamateis very important, since high blood concentrations of glutamate caneasily increase hypothalamic levels as well. One of the earliest andmost consistent findings with exposure to MSG is damage to an area knownas the arcuate nucleus. This small hypothalamic nucleus controls amultitude of neuroendocrine functions, as well as being intimatelyconnected to several other hypothalamic nuclei. It has also beendemonstrated that high concentrations of blood glutamate and aspartate (from foods) can enter the so-called ‘protected brain’ by seeping throughthe unprotected areas, such as the hypothalamus or circumventricularorgans.
Another interesting observation is that chronic elevations of bloodglutamate can even seep through the normal blood-brain barrier whenthese high concentrations are maintained over a long period of time.This, naturally, would be the situation seen when individuals consume,on a daily basis, foods high in the excitotoxins – MSG, aspartame andcysteine. Most experiments cited by the defenders of MSG safety wereconducted to test the efficiency of the BBB acutely. In nature, exceptin the case of metabolic dysfunction ( Such as with ALS), glutamate andaspartate levels are not normally elevated on a daily basis. Sustainedelevations of these excitotoxins are peculiar to the modern diet. ( Andin the ancient diets of the Orientals, but not in as high aconcentration.)
An additional critical factor ignored by the defenders of excitotoxinfood safety is the fact that many people in a large population havedisorders 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 tothe nervous system, collagen-vascular diseases ( lupus), AIDS, braininfections, certain drugs, Alzheimer’s disease, and as a consequence ofnatural aging. There may be many other conditions also associated withbarrier 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 increasebrain concentrations to toxic levels as well. Take for example, multiplesclerosis. We know that when a person with MS has an exacerbation ofsymptoms, the blood-brain barrier near the lesions breaks down, leavingthe surrounding brain vulnerable to excitotoxin entry from the blood,i.e. the diet. But, not only is the adjacent brain vulnerable, but theopenings act as a points of entry, eventually exposing the entire brainto potentially toxic levels of glutamate. Several clinicians haveremarked on seeing MS patients who were made worse following exposure todietary excitotoxins. I have seen this myself.
It is logical to assume that patients with the otherneurodegenerative disorders, such as Alzheimer’s disease, Parkinson’sdisease, and ALS will be made worse on diets high in excitotoxins.Barrier disruption has been demonstrated in the case of Alzheimer’sdisease.
Recently, it has been shown that not only can free radicals open theblood-brain barrier, but excitotoxins can as well. In fact, glutamatereceptors have been demonstrated on the barrier itself. In a carefullydesigned experiment, researchers produced opening of the blood-brainbarrier using injected iron as a free radical generator. When a powerfulfree radical scavenger ( U-74006F) was used in this model, opening ofthe barrier was significantly blocked. But, the glutamate blocker MK-801acted even more effectively to protect the barrier. The authors of thisstudy concluded that glutamate appears to be an important regulator ofbrain capillary transport and stability, and that overstimulation ofNMDA ( glutamate) receptors on the blood-brain barrier appears to playan important role in breakdown of the barrier system. What this alsomeans is that high levels of dietary glutamate or aspartate may verywell disrupt the normal blood-brain barrier, thus allowing moreglutamate to enter the brain, sort of a vicious cycle.
Relation to Cellular Energy Production
Excitotoxin damage is heavily dependent on the energy state of thecell. Cells with a normal energy generation systems that are efficientlyproducing adequate amounts of cellular energy, are very resistant tosuch toxicity. When cells are energy deficient, no matter the cause -hypoxia, starvation, metabolic poisons, hypoglycemia – they becomeinfinitely more susceptible to excitotoxic injury or death. In fact,even normal concentrations of glutamate are toxic to energy deficientcells.
It is known that in many of the neurodegenerative disorders, neuronenergy deficiency often precedes the clinical onset of the disease byyears, if not decades. This has been demonstrated in the case ofHuntington disease and Alzheimer’s disease using the PET scanner, whichmeasures brain metabolism. In the case of Parkinson’s disease, severalgroups have demonstrated that one of the early deficits of the disorderis an impaired energy production by the complex I group of enzymes fromthe mitochondria of the substantia nigra. ( Part of the ElectronTransport System.) Interestingly, it is known that the complex I systemis very sensitive to free radical damage.
Recently, it has been shown that when striatal neurons ( Thoseinvolved in Parkinson’s and Huntington’s diseases.) are exposed tomicroinjected excitotoxins there is a dramatic, and rapid fall in energyproduction by these neurons. CoEnzyme Q10 has been shown, in this model,to restore energy production but not to prevent cellular death. But whencombined with niacinamide, both cellular energy production and neuronprotection is seen. I would recommend for those with neurodegenerativedisorders, a combination of CoQ10, acetyl-L carnitine, niacinamide,riboflavin, methylcobalamin, and thiamine.
One of the newer revelation of modern molecular biology, is thediscovery of mitochondrial diseases, of which cellular energy deficiencyis a hallmark. In many of these disorders, significant clinicalimprovement has been seen following a similar regimen of vitaminscombined with CoQ10 and L-carnitine. Acetyl L-carnitine enters the brainin higher concentrations and also increases brain acetylcholine,necessary for normal memory function. While these particular substanceshave been found to significantly boost brain energy function they arenot alone in this important property. Phosphotidyl serine, GinkgoBiloba, vitamin B12, folate, magnesium, Vitamin K and several others arealso being shown to be important.
While mitochrondial dysfunction is important in explaining why someare more vulnerable to excitotoxin damage than others, it does notexplain injury in those with normal cellular metabolism. There areseveral conditions under which energy metabolism is impaired. Forexample, approximately one third of Americans suffer from what is knownas reactive hypoglycemia. That is, they respond to a meal composed ofeither simple sugars or carbohydrates that are quickly broken down intosimple sugars ( a high glycemic index.) by secreting excessive amountsof insulin. This causes a dramatic lowering of the blood sugar.
When the blood sugar falls, the body responds by releasing a burst ofepinephrine from the adrenal glands, in an effort to raise the bloodsugar. We feel this release as nervousness, palpitations of our heart,tremulousness, and profuse sweating. Occasionally, one can have a slowerfall in the blood sugar that will not produce a reactive release ofepinephrine, thereby producing few symptoms. This can be more dangerous,since we are unaware that our glucose reserve is falling until wedevelop obvious neurological symptoms, such as difficulty thinking and asensation of lightheadedness.
The brain is one of the most glucose dependent organs known, since ithas a limited ability to burn other substrates such as fats. There issome evidence that several of the neurodegenerative diseases are relatedto either excessive insulin release, as with Alzheimer’s disease, orimpaired glucose utilization, as we have seen in the case of Parkinson’sdisease and Huntington’s disease.
It is my firm belief, based on clinical experience and physiologicalprinciples, that many of these diseases occur primarily in the face ofeither reactive hypoglycemia or ‘ brain hypoglycemia’. In at least twowell conducted studies it was found that pure Alzheimer’s dementia wasrare in those with normal blood sugar profiles, and that in most casesAlzheimer’s patients had low blood sugars, and high CSF ( cerebrospinalfluid) insulin levels. In my own limited experience with Parkinson’s andALS patients I have found a disproportionately high number sufferingfrom reactive hypoglycemia.
I found it interesting that several ALS patients have observed anassociation between their symptoms and gluten. That is, when they adhereto a gluten free diet they improve clinically. It may be that byavoiding gluten containing products, such as bread, crackers, cereal,pasta ,etc, they are also avoiding products that are high on theglycemic index, i.e. that produce reactive hypoglycemia. Also, all ofthese food items are high in free iron. Clinically, hypoglycemia willworsen the symptoms of most neurological disorders. We know that severehypoglycemia can, in fact, mimic ALS both clinically and pathologically.It is also known that many of the symptoms of Alzheimer’s diseaseresemble 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 injuriescan trigger biochemical changes that resemble those seen in Alzheimer’spatients. One of the effects of hypoxia is a massive release ofglutamate into the space around the neuron. This results in rapid deathof these sensitized cells. As we age, the blood supply to the brain isfrequently impaired, either because of atherosclerosis or repeatedsyncopal episodes, leading to short periods of hypoxia. Hypoglycemiaproduces lesions very similar to hypoxia and via the same glutamateexcitotoxic mechanism. In fact, recent studies of diabetics sufferingfrom repeated episodes of hypoglycemia associated with over medicationwith insulin, demonstrate brain atrophy and dementia.
Again, it should be realized that excessive glutamate stimulationtriggers a chain of events that in turn triggers the generation of largenumbers of free radical species, both as nitrogen species and oxygenspecies. Once this occurs, especially with the accumulation of thehydroxyl ion, destruction of the lipid components of the membranesoccurs, as lipid peroxidation. In addition, these free radicals damageproteins and DNA as well. The most immediate DNA damage is to themitochondrial DNA, which controls protein expression within thatparticular cell and its progeny. It is suspected that at least some ofthe neurodegenerative diseases, Parkinson’s disease in particular, areinherited in this way. But more importantly, it may be that accumulateddamage to the mitochondrial DNA secondary to progressive free radicalattack ( somatic mitochondrial injury) is the cause of most of theneurodegenerative diseases that are not inherited. This would resultfrom an impaired reserve of antioxidant vitamins/minerals and enzymes,increased cellular stress, chronic infection, free radical generatingmetals and toxins, and impaired DNA repair enzymes.
It is estimated that the number of oxidative free radical injuries toDNA number about 10,000 a day in humans. Normally, these injuries arerepaired by special repair enzymes. It is known that as we age theserepair enzymes decrease or become less efficient. Also, some individualsare born with deficient repair enzymes from birth as, for example, inthe case of xeroderma pigmentosum. Recent studies of Alzheimer’spatients also demonstrate a significant deficiency in DNA repair enzymesand high levels of lipid peroxidation products in the affected parts ofthe brain. It is also important to realize that the hippocampus of thebrain, most severely damaged in Alzheimer’s dementia, is one of the mostvulnerable areas of the brain to low glucose supply as well as lowoxygen supply. That also makes it very susceptible to glutamatetoxicity.
Another interesting finding is that when cells are exposed toglutamate they develop certain inclusions ( cellular debris) that notonly resembles the characteristic neurofibrillary tangles of Alzheimer’sdementia, but are immunologically identical as well. Similarly, whenexperimental animals are exposed to the chemical MPTP, they not onlydevelop Parkinson’s disorder, but the older animals develop the sameinclusions ( Lewy bodies) as see in human Parkinson’s.
Eicosanoids and Excitotoxins
It is known that one of the destructive effects triggered byexcitotoxins is the release of arachidonic acid from the cell membraneand the initiation of the eicosanoid reactions. Remember, glutamateprimarily acts by opening the calcium pore, allowing calcium to pourinto the cell’s interior. Intracellular calcium in high concentrationsinitiates the enzymatic release of arachidonic acid from the cellmembrane, where it is then attacked by two enzymes systems, thecyclooxygenase system and the lipooxgenase system. These in turn producea series of compounds that can damage cell membranes, proteins and DNA,primarily by free radical production, but also directly by the “harmfuleicosanoids.”
Biochemically, we know that high glycemic carbohydrate diets, knownto stimulate the excess release of insulin, can trigger the productionof “harmful eicosanoids.” We should also recognize that simple sugarsare not the only substances that can trigger the release of insulin. Oneof the more powerful triggers includes certain amino acids, includingleucine, alanine, and taurine. Glutamine, while not acting as an insulintrigger itself, markedly potentiates insulin release by leucine. This iswhy, except under certain situations, individual “free” amino acidsshould be avoided.
It is known that excitotoxins can also stimulate the release of these”harmful eicosanoids.” So that in the situation of a hypoglycemicindividual, they would be subjected to production of harmful eicosanoidsdirectly by the high insulin levels, as well as by elevated glutamatelevels. Importantly, both of these events significantly increase freeradical production and hence, lipid peroxidation of cellular membranes.It should be remembered that diets high in arachidonic acid, such as eggyellows, organs meats, and liver, may be harmful to those subjected toexcessive excitotoxin exposure.
And finally, in one carefully conducted experiment, it was shown thatinsulin significantly increases glutamate toxicity in cortical cellcultures and that this magnifying effect was not due to insulin’s effecton glucose metabolism. That is, the effect was directly related toinsulin interaction with cell membranes. Interestingly, insulinincreased toxic sensitivity to other excitotoxins as well.
The Special Role of Flavanoids
Flavonoids are diphenylpropanoids found in all plant foods. They areknown to be strong antioxidants and free radical scavengers. There arethree major flavonols – quercetin, Kaempferol, and myricetin, and twomajor flavones – luteolin and apigenin. Seventy percent of the flavonoidintake in the average diet consist of quercetin, the main source ofwhich is tea ( 49%), onions ( 29%), and apples ( 7%). Fortunately,flavonoids are heat stable, that is, they are not destroyed duringcooking. Other important flavonoids include catechin,leucoanthocyanidins, anthocyanins, hesperedin and naringenin.
Most interest in the flavonoids stemmed from their ability to inhibittumor initiation and growth. This was especially true of quercetin andnaringenin, but also seen with hesperetin and the isoflavone, genistein.There appears to be a strong correlation between their anticarcinogenicpotential and their ability to squelch free radicals. But, in the caseof genistein and quercetin, it also has to do with their ability toinhibit tyrosine kinase and phosphoinositide phosphorylase, bothnecessary for mammary cancer and glioblastoma ( a highly malignant braintumor) growth and development.
As we have seen, there is a close correlation between insulin,excitotoxins, free radicals and eicosanoid production. Of particularinterest, is the finding that most of the flavonoids, especiallyquercetin, are potent and selective inhibitors of delta-5-lipooxygenaseenzyme which initiates the production of eicosanods. Flavones are alsopotent and selective inhibitors of the enzyme cyclooxygenase ( COX)which is responsible for the production of thromboxane A2, one of the”harmful eicosanoids”. The COX-2 enzymes is associated only withexcitatory type neurons in the brain and appears to play a major role inneurodegeneration.
One of the critical steps in the production of eicosanoids is theliberation of arachidonic acid from the cell membrane by phospholipaseA2. Flavonones such as naringenin ( from grapefruits) and hesperetin (citrus fruits) produce a dose related inhibition of phospholipase A2 (80% inhibition), thereby inhibiting the release of arachidonic acid. Thenon-steroidal anti-inflammatory drugs act similarly to block theproduction of inflammatory eicosanoids.
What makes all of this especially interesting is that recently, twomajor studies have found that not only can non-steroidal anti-inflammatories slow the course of Alzheimer’s disease, but they mayprevent it as well. But, these drugs can have significant side effects,such as GI bleeding, liver and kidney damage. In high doses, theflavonoids have shown a similar ability to reduce “harmful eicosanoid”production and should have the same beneficial effect on theneurodegenerative diseases without the side effects. Also, thesecompounds are powerful free radical scavengers and would be expected toreduce excitotoxicity as well.
But, there is another beneficial effect. There is experimental, aswell as clinical evidence, that the flavonoids can reduce capillaryleakage and strengthen the blood brain barrier. This has been shown tobe true for rutin, hesperedin and some chalcones. Rutin and hesperedinhave also been shown to strengthen capillary walls. In the form ofhesperetin methyl chalcone, the hesperedin molecule is readily solublein water, significantly increasing its absorbability. Black currentshave the highest concentration of hesperetin of any fresh fruit, and ina puree form, is even more potent.
The importance of these compounds again emphasizes the need for highintakes of fruits and vegetables in the diet, and may explain the lowincidence of many of these disorders in strict vegetarians, since thiswould supply a high concentration of flavonoids, carotenoids, vitamins,minerals, and other antioxidants to the body. Normally, the flavonoidsfrom fruits and vegetables are only incompletely absorbed, so thatrelatively high concentrations would be needed to attain the sametherapeutic levels seen in these experiments. Juice Plus allows us toabsorb high, therapeutic concentrations of these flavonoids by a processcalled cryodehydration. This process removes the water and sugar fromfruits and vegetable but retains their flavonoids in a fully functionalstate. Also the process allows one to consume large amounts of fruitsand vegetables that would be impossible with the whole plant.
Iron and Health
For decades we, especially women, have been told that we need extra ironfor health -that it builds healthy blood. But, recent evidence indicatesthat iron and copper may be doing more harm than good in most cases. Ithas been well demonstrated that iron and copper are two of the mostpowerful generators of free radicals. This is because they catalyze theconversion of hydrogen peroxide into the very powerful and destructivehydroxyl radical. It is this radical that does so much damage tomembrane lipids and DNA bases within the cell. It also plays a majorrole in the oxidation of LDL-cholesterol, leading to heart attacks andstrokes.
Males begin to accumulate iron shortly after puberty and by middle agehave 1000mg of stored iron in their bodies. Women, by contrast, becauseof menstruation, have only 300 mg of stored iron. But, after menopausethey begin to rapidly accumulate iron so that by middle age they haveabout 1500 mg of stored iron. It is also known that the brain begins toaccumulate iron with aging. Elevated iron levels are seen with all ofthe neurodegenerative diseases, such as Alzheimer’s dementia,Parkinson’s disease, and ALS. It is thought that this iron triggers freeradical production within the areas of the brain destroyed by thesediseases. For example, the part of the brain destroyed by Parkinson’sdisease, the substantia nigra, has very high levels of free iron.
Normally, the body goes to great trouble to make sure all iron andcopper in the body is combined to a special protein for transport andstorage. But, with several of these diseases, we see a loss of thesetransport and storage proteins. This is where flavonoids come into play.We know that many of the flavonoids ( especially quercitin, rutin,hesperidin, and naringenin) are strong chelators of iron and copper. Infact, drinking iced tea with a meal can reduce iron absorption by asmuch as 87%. But, flavonoids in the diet will not make you irondeficient.
Phosphotidyl serine and Excitotoxity
Recent clinical studies indicate that phophotidyl serine cansignificantly improve the mental functioning of a significant number ofAlzheimer’s patients, especially during the early stages of the disease.We know that the brain normally contains a large concentration ofphosphotidyl serine. Interestingly, this compound has a chemicalstructure similar to L-glutamate, the main excitatory neurotransmitterin the brain. Binding studies show that phosphotidyl serine competeswith L-glutamate for the NMDA type glutamate receptor. What this meansis that phosphotidyl serine is a very effective protectant againstglutamate toxicity. Unfortunately, it is also very expensive.
The Many Functions of Ascorbic Acid
The brain contains one of the highest concentrations of ascorbic acidin the body. Most are aware of its function in connective tissuesynthesis and as a free radical scavenger. But, ascorbic acid has otherfunctions that make it rather unique. Ascorbic acid in solution is apowerful reducing agent where it undergoes rapid oxidation to formdehydroascorbic acid. Oxidation of this compound is accelerated by highph, temperature and some transitional metals, such as iron and copper.The oxidized form of ascorbic acid can promote lipid peroxidation andprotein damage. This is why it is vital that you take antioxidantstogether, since several, such as vitamin E ( as D- alpha-tocopherol) andalpha-lipoic acid, act to regenerate the reduced form of the vitamin.
In man, we know that certain areas of the brain have very highconcentrations of ascorbic acid, such as the nucleus accumbens andhippocampus. The lowest levels are seen in the substantia nigra. Theselevels seem to fluctuate with the electrical activity of the brain.Amphetamine acts to increase ascorbic acid concentration in the corpusstriatum ( basal ganglion area) and decrease it in the hippocampus, thememory imprint area of the brain. Ascorbic acid is known to play a vitalrole in dopamine production as well.
One of the more interesting links has been between the secretion ofthe glutamate neurotransmitter by the brain and the release of ascorbicacid into the extracellular space. This release of ascorbate can also beinduced by systemic administration of glutamate or aspartate, as wouldbe seen in diets high in these excitotoxins . The otherneurotransmitters do not have a similar effect on ascorbic acid release.This effect appears to be an exchange mechanism. That is, the ascorbicacid and glutamate exchange places. Theoretically, high concentration ofascorbic acid in the diet could inhibit glutamate release, lessening therisk of excitotoxic damage. Of equal importance is the free radicalneutralizing effect of ascorbic acid.
There is now substantial evidence that ascorbic acid modulates theelectrophysiological as well as behavioral functioning of the brain. Italso attenuates the behavioral response of rats exposed to amphetamine,which is known to act through an excitatory mechanism. In part, this isdue to the observed binding of ascorbic acid to the glutamate receptor.This could mean that ascorbic acid holds great potential in treatingdisease related to excitotoxic damage. Thus far, there are no studiesrelating ascorbate metabolism in neurodegenerative diseases. There is atleast one report of ascorbic acid deficiency in guineas pigs producinghistopathological changes similar to ALS.
It is known that as we age there is a decline in brain levels ofascorbic acid. When accompanied by a similar decrease in glutathioneperoxidase, we see an accumulation of H202 and hence, elevated levels offree radicals and lipid peroxidation. In one study it was found thatwith age not only does the extracellular concentration of ascorbic aciddecrease but the capacity of the brain ascorbic acid system to respondto oxidative stress is impaired as well.
In terms of its antioxidant activity, vitamin C and E interact insuch a way as to restore each others active antioxidant state. Vitamin Cscavenges oxygen radicals in the aqueous phase and vitamin E in thelipid, chain breaking, phase. The addition of vitamin C suppresses theoxidative consumption of vitamin E almost totally, probably because inthe living organism the vitamin C in the aqueous phase is adjacent tothe lipid membrane layer containing the vitamin E.
When combined, the vitamin C was consumed faster during oxidativestress than the vitamin E. Once the vitamin C was totally consumed, thevitamin E began to be depleted at an accelerated rate. N-acetyl-L-cysteine and glutathione can reduce vitamin E consumption as well, butless effectively than vitamin C. The real danger is when vitamin C iscombined with iron. Recent experiments have shown that such combinationscan produce widespread destruction within the striate areas of thebrain. This is because the free iron oxidizes the ascorbate to producethe powerful free radical hydroxyascorbate. Alpha-lipoic acid actspowerfully to keep the ascorbate and tocopherol in the reduced state (antioxidant state). As we age, we produce less of the transferrintransport protein that normally binds free iron. As a result, olderindividuals have higher levels of free iron within their tissues,including brain.
Conclusion
In this discussion, I tried to highlight some of the more pertinentof the recent findings related to excitotoxicity in general andneurodegenerative diseases specifically. In no way is this an allinclusive discussion of this topic. There are many areas I had to omitbecause of space, such as alpha-lipoic acid, an antioxidant that holdsgreat promise in combatting many of these diseases. Also, I did not gointo detail concerning the metabolic stimulants, the relationshipbetween exercise and degenerative nervous system diseases, theprotective effect of methycobalamin, and the various disorders relatedto excitotoxins.
I also purposely omitted discussions of magnesium to keep this papershort. It is my experience, that magnesium is one of the most importantneuroprotectants known. I would encourage those who suffer from one ofthe excitotoxin related disorders to avoid, as much as possible, foodborne excitotoxin additives and to utilize the substances discussedabove. The fields of excitotoxin research, in combination with researchon free radicals and eicosanoids, are growing very rapidly and newinformation arises daily. Great promise exist in the field of flavonoidresearch as regards many of these neurodegenerative diseases as well asin our efforts to prevent neurodegeneration itself.
A recent study has demonstrated that aspartame feeding to animalsresults in an accumulation of formaldehyde within the cells, withevidence of significant damage to cellular proteins and DNA. In fact,the formaldehyde accumulated with prolonged use of aspartame. With thisdamning evidence, one would have to be suicidal to continue the use ofaspartame sweetened foods, drinks and medicines. The use of foodscontaining excitotoxin additives is especially harmful to the unborn andsmall children. By age 4 the brain is only 80% formed. By age 8, 90% andby age 16 it is fully formed, but still undergoing changes and rewiring( plasticity). We know that the excitotoxins have a devastating effecton formation of the brain ( wiring of the brain) and that such exposurecan cause the brain to be “miswired.” This may explain the significant,almost explosive increase in ADD and ADHD. Glutamate feeding to pregnantanimals produces a syndrome almost identical to ADD. It has also beenshown that a single feeding of MSG after birth can increase freeradicals in the offspring’s brain that last until adolescence.Experimentally, we known that infants are 4X more sensitive to thetoxicity of excitotoxins than are adults. And, of all the speciesstudied, cats, dogs, primates, chickens, guinea pigs, and rats, humansare by far the most sensitive to glutamate toxicity. In fact, they are5x more sensitive than rats and 20x more sensitive than non-humanprimates.
I have been impressed with the dramatic improvement in children withADD and ADHD following abstention from excitotoxin use. It requires caremonitoring of these children. Each time they are exposed to thesesubstances, they literally go bonkers. It is ludicrous, with all we knowabout the destructive effects of excitotoxins, to continue to allowourselves and our children to continue on this destructive path.
USED BY PERMISSION OF THE AUTHOR
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Dr. Russell L. Blaylock answers these questions and poses some startling evidence as to the eventual consequences of a heavy MSG-diet in his book _Excitotoxins: The Taste that Kills_. In basic terms, MSG (and other, similar agents) pierces the blood-brain barrier and over-stimulates the neurons of a brain to a deadly degree. Habitual intake among animal experiments has shown the development of tumors, memory loss, and a whole host of neurodegenerative diseases as the end result of excess excitotoxin intake, including Alzhiemer’s, Parkenson’s, Lou Gerhig’s etc. Walk into any gas station in the United States (or grocery store, for that matter) and, upon close investigation, you will find that 75%-90% of the available food has been ‘enhanced’ to some degree by excitotoxins. The chemical agents are often disguised by such ambiguous terms as ‘spice’ and ‘natural flavors’ or, my personal favorite, ‘hydrolyzed vegetable protein.’ A consumer society must have consumer slaves to keep it functioning; MSG is the crack cocaine of the food industry…and it is legally perpetuated by slush-fund advocates and a pork-glutted FDA. As proven again and again, money talks, … [you can finish the maxim for me]. Blaylock’s thesis is written in a technical style, but the use of repetition throughout each chapter hammer in his myriad points into the reader with precision and power. An important book for anyone concerned with the health of self and family. You are what you eat—but do you know _what_ it is you are eating, below the surface of taste/fulfillment? |
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