Thursday, August 28, 2008

Part 8 Excitotoxins, Neurodegeneration and Neurodevelopment

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


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.