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such a way as to restore each other's active antioxidant state. in hippocampal neurons. It is interesting to note that glutamate Vitamin C scavenges oxygen radicals in the aqueous phase and can produce classic toxicity in the immature brain, even before vitamin E in the lipid, chain-breaking phase. The addition of vita- the glutamate receptors develop. High glutamate levels can also min C suppresses the oxidative consumption of vitamin E almost affect astroglial proliferation as well as neuronal differentiation. totally, probably because in the living organism the vitamin C in It appears to act via the phosphoinositide protein kinase C path- the aqueous phase is adjacent to the lipid membrane layer contain- way. ing the vitamin E. It has been shown that during brain development there is an When combined, the vitamin C is consumed faster during overgrowth of neuronal connections and cellularity, and that at oxidative stress than is vitamin E. Once the vitamin C is totally this stage there is a peak in levels of brain glutamate, whose func- consumed, vitamin E begins to be depleted at an accelerated rate. tion it is to remove excess connections and neuronal overexpres- N-acetyl-L-cysteine and glutathione can reduce vitamin E con- sion. This has been referred to as "pruning". Importantly, gluta- sumption as well, but less effectively mate excess during synaptogenesis and than vitamin C. pathway development has been shown The real danger is when vitamin C to cause abnormal connections in the is combined with iron. This is hypothalamus that can lead to later because the free iron oxidises the Likewise, excess glutamate endocrinopathies.” ascorbate to produce the free radical, In general, toxicological injury in dehydroxyascorbate. Alpha-lipoic can cause neural pathways the developing foetus carries the acid acts powerfully to keep the to produce improper greatest risk during the first two ascorbate and tocopherol in the trimesters. But this is not so for the reduced state (antioxidant state). As connections—a process | call brain, which undergoes a spurt of we age, we produce less of the trans- "miswiring of the brain". growth that begins during the third ferrin transport protein that normally trimester and continues at least two binds free iron. As a result, older years after birth. Dendritic growth is individuals have higher levels of free maximal in the late foetal period to iron within their tissues, including one year of age, but may continue at a brain, and are therefore at greater risk slower pace for several more years. of widespread free radical injury. Neurotransmitter development also begins during the late foetal period, but continues for as long as four years after birth. This IMPLICATIONS FOR NEURODEVELOPMENT means that alterations in dietary glutamate and aspartate are espe- Recent studies have shown that glutamate plays a vital role in cially dangerous to the foetus during pregnancy and for several the development of the nervous system, especially as regards neu- years after birth. ronal survival, growth and differentiation, development of circuits The developing brain's susceptibility to excitotoxicity varies, and cytoarchitecture.* since each brain region has a distinct developmental profile. The For example, it is known that deficiencies of glutamate in the type of excitotoxin also appears to matter. For example, kianate is brain during neurogenesis can result in maldevelopment of the non-toxic to the immature brain but extremely toxic to the mature visual cortices and may play a role in the development of schizo- brain. The glutamate agonist NMDA is especially toxic up to post- phrenia.” Likewise, excess glutamate can cause neural pathways natal day seven, while quisqualate and AMPA have peak toxicity to produce improper connections—a process | call "miswiring of from postnatal day seven through fourteen. L-cysteine is a power- the brain". Excess glutamate during embryogenesis has been ful excitotoxin on the immature brain. shown to reduce dendritic length and suppress axonal outgrowth Myelination can also be affected by neurotoxins. In general, Likewise, excess glutamate can cause neural pathways ae ee to produce improper connections—a process | call "miswiring of the brain”. IMPLICATIONS FOR NEURODEVELOPMENT Recent studies have shown that glutamate plays a vital role in the development of the nervous system, especially as regards neu- ronal survival, growth and differentiation, development of circuits and cytoarchitecture.* 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 schizo- phrenia.” 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 Endnotes 50. Greenemyer, J.T., "Neuronal bioenergetics 56. Bucht, G. et al., ibid. 44. Toth, E. and Lajtha, A., "Elevation of cere- defects, excitotoxicity and Alzheimer's disease: 57. Fujiasawa, Y., Saki, K. and Akiyama, K., bral levels of nonessential amino acids in vivo by __ Use it or lose it", Neurobiol. Aging 12:334-336, "Increased insulin levels after OGTT load in administration of large doses", Neurochem. Res. 1991. peripheral blood and cerebrospinal fluid of 6:1309-1317, 1981. 51. Parker, W.D., Boyson, S.J. and Parks, J.K., patients with dementia of the Alzheimer's type", 45. Dowling, P., Husar, W. et al., "Cell death "Abnormalities of the electron transport chain in Bio. Psych. 30:1219-1228, 1991. and birth in multiple sclerosis brain", J. Neurol. idiopathic Parkinson's disease", Ann. Neurol. 58. Gotoh, F., Kitamura, A. et al., "Abnormal Sci. 149:1-11, 1997. 26:719-723, 1989. insulin secretion in amyotrophic lateral sclero- 46. Bennow, K. et al., "Blood-brain barrier dis- 52. Schapira, A.H.V., Mann, V.M. et al., sis", J. Neurol. Sci. 16:201-207, 1972. turbance in patients with Alzheimer's disease is "Mitochondrial function in Parkinson's disease", 59. Pettgrew, J.W. et al., "The role of mem- related to vascular factors", Acta. Neuro. Scand. Ann. Neurol. 32:5116-S124, 1992. branes and energetics in Alzheimer's disease", in 81:323-326, 1990. 47. Zuccarello, M. and Anderson, D.K., "Interactions between free radicals and excitatory amino acids in the blood-brain barrier disruption Terry, R.D. et al. (eds), Alzheimer's Disease, Raven Press, New York, 1994. 60. Leibson, C.L., Rocca, W.A. et al., "Risk of dementia among persons with diabetes mellitus: 53. Beal, M.-F. et al., "Coenzyme Q10 and niaci- namide are protective against mitochondrial tox- ins in vivo", Neuro. 44(Supp2):A177, April ra 1994. . after iron injury in the rat", J. Neurotrauma : a population-based cohort study", Am. J. 10.397 481, 1993, 34. Calvani, M., Koverech, A. and Carurso,G., — Eyidemiol, 145:301-308, 1997. 48. Koenig, H. et al., "Capillary NMDA recep- _""eatment of mitochondrial diseases", in 61. Kalaria, R.N. and Harik, S.L, "Reduced glu- tors regulate blood-brain barrier function and DiMauro, S. and Wallace, D.C. (eds), cose transporter at the blood-brain barrier and in breakdown" [source not cited] 588:297-303, Mitochondrial DNA in Human Pathology, Raven the cerebral cortex in Alzheimer's disease", J. 1992. Press, New York, 1993, pp. 173-198. Neurochem. 53:1083-1088, 1989. 49. Novelli, A., Reilly, J.A. et al., "Glutamate 55. Bucht, G. et al., "Changes in blood glucose 62. Kaleria, R.N. et al., "The glucose transporter becomes neurotoxic via the N-methy]-D aspar- and insulin secretion in patients with senile of the human brain and blood brain barrier", Ann. tate receptor when intracellular energy levels are dementia of Alzheimer's type", Acta. Medica Neurol. 24:757-764, 1988. reduced", Brain Res. 451:205-207, 1988. Scand. 213:387-392, 1983. 63. Tannaka, M., Kovalenko, S.A. et al., 44 - NEXUS AUGUST - SEPTEMBER 2000