Part 8 Excitotoxins, Neurodegeneration and Neurodevelopment

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

Neurodevelopment

Recent studies have shown that glutamate plays a vital role in the development of the nervous system, especially as regards neuronal survival, growth and differentiation, development of circuits and cytoarchitecture.78 For example, it is known that deficiencies of glutamate in the brain during neurogenesis can result in maldevelopment of the visual cortices and may play a role in the development of schizophrenia.79 Likewise, excess glutamate can cause neural pathways to produce improper connections, a process I call " miswiring of the brain". Excess glutamate during embryogenesis has been shown to reduce dendritic length and suppress axonal outgrowth in hippocampal neurons. It is interesting to note that glutamate can produce classic toxicity in the immature brain even before the glutamate receptors develop. High glutamate levels can also affect astroglial proliferation as well as neuronal differentiation. It appears to act via the phosphoinositide protein kinase C pathway.

It has been shown that during brain development there is an overgrowth of neuronal connections and cellularity, and that at this stage there is a peak in brain glutamate levels whose function it is to remove excess connections and neuronal overexpression. This has been referred to as " pruning". Importantly, glutamate excess during synaptogenesis and pathway development has been shown to cause abnormal connections in the hypothalamus that can lead to later endocrinopathies.80

In general, toxicological injury in the developing fetus carries the greatest risk during the first two trimesters. But, this is not so for the brain, which undergoes a spurt of growth that begins during the third trimester and continues at least two years after birth. Dendritic growth is maximal in the late fetal period to one year of age, but may continue at a slower pace for several more years. Neurotransmitter development also begins during the late fetal period but continues for as long as four years after birth. This means that alterations in dietary glutamate and aspartate are especially dangerous to the fetus during pregnancy and for several years after birth. The developing brain's succeptability to excitotoxicity varies , since each brain region has a distinct developmental profile. The type of excitotoxin also appears to matter. For example, kianate is non-toxic to the immature brain but extremely toxic to the mature brain. The glutamate agonist, NMDA, is especially toxic up to postnatal day seven while quisqualate and AMPA have peak toxicity from postnatal day seven through fourteen. L-cysteine is a powerful excitotoxin on the immature brain.

Myelination can also be affected by neurotoxins. In general, excitotoxic substances affect dendrites and neurons more than axons but axon demyelination has been demonstrated. During the myelination process, each fiber tract has its own spatiotemporal pattern of development, accompanied by significant biochemical changes, especially in lipid metabolism. More recent studies have shown an even more complicated pattern of CNS myelination than previously thought. This is of importance especially as regards the widespread use of aspartame, because of this triple toxin's effects on neuronal proteins and DNA. Of special concern is aspartame's methanol component and its breakdown product, formaldehyde.81 Also, it is known that the aspartate moiety undergoes spontanous racemization in hot liquids to form D-aspartate, which has been associated with tau proteins in Alzheimer's disease.82-83

As you can see, the development of the brain is a very complex process that occurs in a spatial and temporal sequence that is carefully controlled by biochemical, structural, as well as neurophysiological events. Even subtle changes in these parameters can produce ultimate changes in brain function that may vary from subtle alteration in behavior and learning to autism, attention deficit disorder and violence dyscontrol.84, 85, 86

Experiments in which infant animals were exposed to MSG, have demonstrated significant neurobehavioral deficits.87-88 Other studies have shown that when pregnant female animals were fed MSG their offspring demonstrated normal simple learning but showed significant deficits in complex learning, accompanied by profound reductions in several forebrain neurotransmitters.89-90 In human this would mean that during infancy and early adolescence learning would appear normal, but with entry into a more advance education level, learning would be significantly impaired. In several ways, this animal model resembles ADD and ADHD in humans. Kubo and co-workers found that neonatal glutamate could severely injure hippocampal CA1 neurons and dendrites and, as a result, impair discriminative learning in rats.91

It is also important to note that neonatal exposure to MSG has been shown to cause significant alterations in neuroendocrine function that can be prolonged.92-93 By acting on the hypothalamus and its connections to the remainder of the limbic connections, excitotoxins can profoundly affect behavior.

Part 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.