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iron, the peroxide is converted into the dangerous and very pow- potency than D-alpha-tocopherol. Stanley Fahn found that a com- erful free radical, hydroxide. As the hydroxide radical diffuses bination of D-alpha-tocopherol and ascorbic acid in high doses throughout the cell, destruction of the lipid components of the cell reduced progression of the disease by 2.5 years.” Tocotrienol may takes place—a process called "lipid peroxidation". Of equal have even greater benefits, especially when used in combination importance is the generation of the powerful peroxynitrite radical, with other antioxidants. There is some clinical evidence, including which has been shown to produce serious injury in cellular pro- my own observations, that vitamin E, especially in the form of D- teins and DNA, both mitochondrial and nuclear.” alpha-tocopherol, also slows the course of ALS. I would caution Using a laser microprobe mass analyser, researchers discovered that antioxidants work best in combination, and that when used that iron accumulation in Parkinson's disease is primarily separately can have opposite, harmful effects. That is, when localised in the neuromelanin granules (which gives the nucleus antioxidants, such as ascorbic acid and alpha-tocopherol, become its black colour). Other studies showed that there is dramatic oxidised themselves—such as in the case of dehydroascorbic accumulation of aluminium within these granules.” Most likely, acid—they no longer protect, but rather act as free radicals them- the aluminium displaces the bound iron, releasing highly reactive selves. The same is true of alpha-tocopherol.” free iron. It is known that even low concentrations of aluminium Again, it should be realised that excessive glutamate stimula- salts can enhance iron-induced lipid peroxidation by almost an tion triggers a chain of events that in turn sparks the generation of order of magnitude. Further, direct infusion of iron into the sub- large numbers of free radical species, both as nitrogen and oxy- stantia nigra nucleus in rodents can induce a parkinsonian syn- gen. These free radicals have been shown to damage cellular pro- drome and a dose-related decline in dopamine. Recent studies teins (protein carbonyl products) and DNA. The most immediate indicate that individuals having Parkinson's disease also have DNA damage is to the mitochondrial DNA, which controls pro- defective iron metabolism.”* tein expression within that particular cell Another early finding in Parkinson's dis- and its progeny, producing rather profound ease is the reduction in complex I enzymes changes in cellular energy production. It is within the mitochondria of this nucleus.” It suspected that at least some of the neurode- is well known that the complex I enzymes generative diseases, Parkinson's disease in are partiowan'y sensitive to tree radical What has been shown Particuat, are affected in this way injury. These enzymes are critical to the pro- . sai ronic free radical accumulation wou duction of cellular energy. As we shall see, in all these studies Isa result in an impaired functional reserve of wen celular energy is decreased the toxic direct connection antioxidant viamins, minerals enzymes and effect of excitatory amino acids increases . os thiol compounds necessary for neural pro- dramatically. between excitotoxicity tection. Chronic unrelieved stress, chronic In the case of ALS, there is growing evi- and free radical infection, free-radical-generating metals and dence that similar free radical damage, most generation in a toxins, and impaired DNA repair enzymes likely triggered by toxic concentrations of all add to this damage. excitotoxins, plays a major role in the disor- multitude of diseases We know there are four main endogenous sources of oxidants: 1. Those produced naturally from aerobic metabolism of glucose. 2. Those produced during phago- cytic cell attack on bacteria, viruses and parasites, especially with chronic infec- tions. 3. Those produced during the degra- dation of fatty acids and other mole- cules that produce HO: as a by-prod- uct. (This is important in stress, which has been shown to increase brain levels of free radicals significantly.) der.*® Several studies demonstrated lipid peroxidation product accumulation within the spinal cords of ALS victims, as well as iron accumulation.’! It is now known that glutamate acts on its receptor via a nitric oxide mecha- nism.” Overstimulation of the gluta- mate receptor can produce an accumu- lation of reactive nitrogen species, resulting in the generation of several species of dangerous free radicals, including peroxynitrite. There is grow- ing evidence that, at least in part, this is how excess glutamate damages nerve 4. Oxidants produced during the cells.* In a multitude of studies, a close course of p450 degradation of natural link was demonstrated between excitotoxicity and free radical toxins. And, as we have seen, one of the major endogenous and disorders such as seizures, strokes, brain trauma, viral infections and neurodegenerative diseases. generation.” sources of free radicals is from the exposure of tissues to free iron, Other studies showed that certain free radical scavengers especially in the presence of ascorbate. Unfortunately, iron is one (antioxidants) successfully block excitotoxic destruction of neu- mineral heavily promoted by the health industry, and is frequently rons. For example, vitamin E is known to block glutamate toxici- added to many foods, especially breads and pastas. Copper is also ty completely in vitro.* Whether it is as efficient in vivo is not a powerful free radical generator and has been shown to be known. But it is interesting in the light of recent observations that elevated within the substantia nigra of parkinsonian brains.” vitamin E, combined with other antioxidant vitamins, slows the What has been shown in all these studies is a direct connection course of Alzheimer's disease and is suggested to reduce the rate between excitotoxicity and free radical generation in a multitude of advance in a subgroup Parkinson's disease as well. of diseases and disorders such as seizures, strokes, brain trauma, In the Datatop study of the effect of alpha-tocopherol alone, no viral infections and neurodegenerative diseases. reduction in disease progression was seen. The problem with this Interestingly, free radicals were shown to prevent glutamate study was the low dose that was used and the fact that the DL- Continued on page 81 alpha-tocopherol used is known to have a much lower antioxidant generation ina multitude of diseases seizures, strokes, brain trauma, viral infections diseases. 36 = NEXUS JUNE — JULY 2000 What has been shown in all these studies isa direct connection between excitotoxicity and free radical and disorders such as and neurodegenerative Continued on page 81