Part 9 Excitotoxins, Neurodegeneration and Neurodevelopment

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

Conclusion

In this brief discussion of a most complicated and evolving subject I have had to omit several important pieces of the puzzle. For example, I have said little about the functional components of the receptor systems, the glutamate transporter and its relation to ALS and Alzheimer's dementia, receptor decay with aging and disease, membrane effects of lipid peroxidation products, membrane fluidity, effects of chronic inflammation on the glutamate/free radical cycle, stress hormones and excitotoxicity, the role of insulin excess on the eicosanoid system, or the detailed physiology of the glutamatergic system. I have also only briefly alluded to the toxicity of aspartame and omitted its strong connection to brain tumor induction.

But, I have tried to show the reader that there is a strong connection between dietary and indogenous excitotoxin excess and neurological dysfunction and disease. Many of the arguments by the food processing industry has been shown to be false. For example, that dietary glutamate does not enter the brain because of exclusion by the blood-brain barrier, has been shown to be wrong, since glutamate can enter by way of the unprotected areas of the brain such as the circumventricular organs. Also, as we have seen, chronic elevations of blood glutamate can breech the intact blood-brain barrier. In addition, there are numerous conditions under which the barrier is made incompetent.

As our knowledge of the pathophysiology and biochemistry of the neurodegenerative diseases increases, the connection to excitotoxicity has become stonger.94 This is especially so with the interrelationship between excitotoxicity and free radical generation and declining energy production with aging. Several factors of aging have been shown to magnify this process. For example, as the brain ages its iron content increases, making it more susceptible to free radical generation. Also , aging changes in the blood brain barrier, micovascular changes leading to impaired blood flow, free radical mitochondrial injury to energy generating enzymes, DNA adduct formation, alterations in glucose and glutamate transporters and free radical and lipid peroxidation induced alterations in the neuronal membranes all act to make the aging brain increasingly susceptible to excitotoxic injury.

Over a lifetime of free radical injury due to chronic stress, infections, trauma, impaired blood flow, hypoglycemia, hypoxia and poor antioxidant defenses secondary to poor nutritional intake, the nervous system is significantly weakened and made more susceptible to further excitotoxic injury. We known that a loss of neuronal energy generation is one of the early changes seen with the neurodegenerative diseases. This occurs long before clinical disease develops. But, even earlier is a loss of neuronal glutathione functional levels.

I included the material about the special function of ascorbic acid because few are aware of the importance of adequate ascorbate levels for CNS function and neural protection against excitotoxicity. As we have seen, it plays a vital role in neurobehavioral regulation and the dopaminergic system as well,which may link ascorbate supplementation to improvements in schizophrenia.

Our knowledge of this process opens up new avenues for treatment as well as prevention of excitotoxic injury to the nervous system. For example, there are many nutritional ways to improve CNS antioxidant defenses and boost neuronal energy generation, as well as improve membrane fluidity and receptor integrity. By using selective glutamate blocking drugs or nutrients, one may be able to alter some of the more devastating effects of Parkinson's disease. For example, there is evidence that dopamine deficiency causes a disinhibition (overactivity) of the subthalamic nucleus and that this may result in excitotoxic injury to the substantia nigra.95 By blocking the glutamatergic neurons in this nucleus, one may be able to reduce this damage. There is also evidence that several nutrients can significantly reduce excitotoxicity. For example, combinations of coenzyme Q10 and niacinamide have been shown to protect against striatal excitotoxic lesions. Methylcobolamine, phosphotidylserine, picnogenol and acetyl-L-carnitine all protect against excitotoxicity as well.

Of particular concern is the toxic effects of these excitotoxic compounds on the developing brain. It is well recognized that the immature brain is four times more sensitive to the toxic effects of the excitatory amino acids as is the mature brain.This means that excitotoxic injury is of special concern from the fetal stage to adolescence. There is evidence that the placenta concentrates several of these toxic amino acids on the fetal side of the placenta. Consumption of aspartame and MSG containing products by pregnant women during this critical period of brain formation is of special concern and should be discouraged. Many of the effects, such as endocrine dysfunction and complex learning, are subtle and may not appear until the child is older. Other hypothalamic syndromes associated with early excitotoxic lesions include immune alterations and violence dyscontrol.

Over 100 million American now consume aspartame products and a greater number consume products containing one or more excitotoxins. There is sufficient medical literature documenting serious injury by these additives in the concentrations presently in our food supply to justify warning the public of these dangers. The case against aspartame is especially strong.

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Part 7 Excitotoxins, Neurodegeneration and Neurodevelopment

Part 7 Excitotoxins, Neurodegeneration and Neurodevelopment By Russell L. Blaylock, M.D

Special Functions of Ascorbic Acid

The brain contains one of the highest concentrations of ascorbic acid in the body. Most are aware of ascorbic acid's function in connective tissue synthesis and as a free radical scavenger. But, ascorbic acid has other functions that make it rather unique.

In man, we know that certain areas of the brain have very high concentrations of ascorbic acid, such as the nucleus accumbens and hippocampus. The lowest levels are seen in the substantia nigra.72 These levels seem to fluctuate with the electrical activity of the brain. Amphetamine acts to increase ascorbic acid concentration in the corpus striatum ( basal ganglion area) and decrease it in the hippocampus, the memory imprint area of the brain. Ascorbic acid is known to play a vital role in dopamine production as well.

One of the more interesting links has been between the secretion of the glutamate neurotransmitter by the brain and the release of ascorbic acid into the extracellular space.73 This release of ascorbate can also be induced by systemic administration of glutamate or aspartate, as would be seen in diets high in these excitotoxins . The other neurotransmitters do not have a similar effect on ascorbic acid release. This effect appears to be an exchange mechanism. That is, the ascorbic acid and glutamate exchange places. Theoretically, high concentration of ascorbic acid in the diet could inhibit glutamate release, lessening the risk of excitotoxic damage. Of equal importance is the free radical neutralizing effect of ascorbic acid.

There is now substantial evidence that ascorbic acid modulates the electrophysiological as well as behavioral functioning of the brain.74 It also attenuates the behavioral response of rats exposed to amphetamine, which is known to act through an excitatory mechanism.75 In part, this is due to the observed binding of ascorbic acid to the glutamate receptor. This could mean that ascorbic acid holds great potential in treating disease related to excitotoxic damage. Thus far, there are no studies relating ascorbate metabolism in neurodegenerative diseases. There is at least one report of ascorbic acid deficiency in guineas pigs producing histopathological changes similar to ALS.76

It is known that as we age there is a decline in brain levels of ascorbate. When accompanied by a similar decrease in glutathione peroxidase, we see an accumulation of h302 and hence, elevated levels of free radicals and lipid peroxidation. In one study, it was found that with age not only does the extracellular concentration of ascorbic acid decrease but the capacity of the brain ascorbic acid system to respond to oxidative stress is impaired as well.77

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

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

Part 5 Excitotoxins, Neurodegeneration and Neurodevelopment

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

The Blood-Brain Barrier

One of the MSG industry's chief arguments for the safety of their product is that glutamate in the blood cannot enter the brain because of the blood-brain barrier ( BBB), a system of specialized capillary structures designed to exclude toxic substance from entering the brain. There are several criticisms of their defense. For example, it is known that the brain, even in the adult, has several areas that normally do not have a barrier system, called the circumventricular organs. These include the hypothalamus, the subfornical organ, organium vasculosum, area postrema, pineal gland, and the subcommisural organ. Of these, the most important is the hypothalamus, since it is the controlling center for all neuroendocrine regulation, sleep wake cycles, emotional control, caloric intake regulation, immune system regulation and regulation of the autonomic nervous system. As stated, glutamate is the most important neurotransmitter in the hypothalamus. Therefore, careful regulation of blood levels of glutamate is very important, since high blood concentrations of glutamate would be expected to increase hypothalamic levels as well. One of the earliest and most consistent findings with exposure to MSG is damage to an area of the hypothalamus known as the arcuate nucleus.This small hypothalamic nucleus controls a multitude of neuroendocrine functions, as well as being intimately connected to several other hypothalamic nuclei. It has also been demonstrated that high concentrations of blood glutamate and aspartate ( from foods) can enter the so-called "protected brain" by seeping through the unprotected areas, such as the hypothalamus or other circumventricular organs.
Another interesting observation is that chronic elevations of blood glutamate can even seep through the normal blood-brain barrier when these high concentrations are maintained over a long period of time.44 This would be the situation seen when individuals consume, on a daily basis, foods high in the excitotoxins - MSG, aspartame and L-cysteine. Most experiments cited by the defenders of MSG safety were conducted to test the efficiency of the BBB acutely. In nature, except in the case of metabolic dysfunction ( such as with ALS), glutamate and aspartate levels are not normally elevated on a continuous basis. Sustained elevations of these excitotoxins are peculiar to the modern diet. ( and in the ancient diets of the Orientals, but not in as high a concentration.)

An additional critical factor ignored by the defenders of excitotoxin food safety is the fact that many people in a large population have disorders known to alter the permeability of the blood-brain barrier. The list of condition associated with barrier disruption include: hypertension, diabetes, ministrokes, major strokes, head trauma, multiple sclerosis, brain tumors, chemotherapy, radiation treatments to the nervous system, collagen-vascular diseases ( lupus), AIDS, brain infections, certain drugs, Alzheimer's disease, and as a consequence of natural aging. There may be many other conditions also associated with barrier disruption that are as yet not known.

When the barrier is dysfunctional due to one of these conditions, brain levels of glutamate and aspartate reflect blood levels. That is, foods containing high concentrations of these excitotoxins will increase brain concentrations to toxic levels as well. Take for example, multiple sclerosis. We know that when a person with MS has an exacerbation of symptoms, the blood-brain barrier near the lesions breaks down, leaving the surrounding brain vulnerable to excitotoxin entry from the blood, i.e. the diet.45 But, not only is the adjacent brain vulnerable, but the openings act as points of entry, eventually exposing the entire brain to potentially toxic levels of glutamate. Several clinicians have remarked that their MS patients were made worse following exposure to dietary excitotoxins. I have seen this myself. It is logical to assume that patients with the other neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and ALS will be made worse on diets high in excitotoxins. Barrier disruption has been demonstrated in the case of Alzheimer's disease.46

Recently, it has been shown that not only can free radicals open the blood-brain barrier, but excitotoxins can as well.47 In fact, glutamate receptors have been demonstrated on the barrier itself.49 In a carefully designed experiment, researchers produced opening of the blood-brain barrier using injected iron as a free radical generator. When a powerful free radical scavenger (U-74006F) was used in this model, opening of the barrier was significantly blocked. But, the glutamate blocker MK-801 acted even more effectively to protect the barrier. The authors of this study concluded that glutamate appears to be an important regulator of brain capillary transport and stability, and that overstimulation of NMDA ( glutamate) receptors on the blood-brain barrier appears to play an important role in breakdown of the barrier system. What this also means is that high levels of dietary glutamate or aspartate may very well disrupt the normal blood-brain barrier, thus allowing more glutamate to enter the brain, creating a vicious cycle.