Part 4 Excitotoxins, Neurodegeneration and NeurodevelopmentBy Russell L. Blaylock, M.D
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The Free Radical Connection
It is interesting to note that many of the same neurological diseases associated with excitotoxic injury are also associated with accumulations of toxic free radicals and destructive lipid oxidation products.19 For example, the brains of Alzheimer's disease patients have been found to contain high concentration of lipid peroxidation products and evidence of free radical accumulation and damage. 20,21,22
In the case of Parkinson's disease, we know that one of the early changes is the loss of one of the primary antioxidant defense systems, glutathione, from the neurons of the striate system, and especially in the substantia nigra.23 It is this nucleus that is primarily affected in this disorder. Accompanying this, is an accumulation of free iron, which is one of the most powerful free radical generators known.24 One of the highest concentrations of iron in the body is within the globus pallidus and the substantia nigra. The neurons within the latter are especially vulnerable to oxidant stress because the catabolic metabolism of the transmitter-dopamine- can proceed to the creation of very powerful free radicals.That is, it can auto-oxidize to peroxide,which is normally detoxified by glutathione. As we have seen, glutathione loss in the substantia nigra is one of the earliest deficiencies seen in Parkinson's disease. In the presence of high concentrations of free iron, the peroxide is converted into the dangerous, and very powerful free radical, hydroxide. As the hydroxide radical diffuses throughout the cell, destruction of the lipid components of the cell takes place, a process called lipid peroxidation. Of equal importance is the generation of the powerful peroxynitrite radical, which has been shown to produce serious injury to cellular proteins and DNA, both mitochondrial and nuclear.25
Using a laser microprobe mass analyzer, researchers have recently discovered that iron accumulation in Parkinson's disease is primarily localized in the neuromelanin granules ( which gives the nucleus its black color).26 It has also been shown that there is dramatic accumulation of aluminum within these granules.27 Most likely, the aluminum displaces the bound iron, releasing highly reactive free iron. It is known that even low concentrations of aluminum salts can enhance iron-induced lipid peroxidation by almost an order of magnitude. Further, direct infusion of iron into the substantia nigra nucleus in rodents can induce a Parkinsonian syndrome, and a dose related decline in dopamine. Recent studies indicate that individuals having Parkinson's disease also have defective iron metabolism.28
Another early finding in Parkinson's disease is the reduction in complex I enzymes within the mitochondria of this nucleus.29 It is well known that the complex I enzymes are particularly sensitive to free radical injury. These enzymes are critical to the production of cellular energy. As we shall see, when cellular energy is decreased, the toxic effect of excitatory amino acids increases dramatically.
In the case of ALS there is growing evidence that similar free radical damage, most likely triggered by toxic concentrations of excitotoxins, plays a major role in the disorder.30 Several studies have demonstrated lipid peroxidation product accumulation within the spinal cords of ALS victims as well as iron accumulation.31
It is now known that glutamate acts on its receptor via a nitric oxide mechanism.32 Overstimulation of the glutamate receptor can produce an accumulation of reactive nitrogen species, resulting in the generation of several species of dangerous free radicals, including peroxynitrite. There is growing evidence that, at least in part, this is how excess glutamate damages nerve cells.33 In a multitude of studies, a close link has been demonstrated between excitotoxicity and free radical generation.34-37
Others have shown that certain free radical scavengers (antioxidants), have successfully blocked excitotoxic destruction of neurons. For example, vitamin E is known to completely block glutamate toxicity in vitro.38 Whether it will be as efficient in vivo is not known. But, it is interesting in light of the recent observations that vitamin E combined with other antioxidant vitamins slows the course of Alzheimer's disease and has been suggested to reduce the rate of advance in a subgroup Parkinson's disease patients as well. In the DATATOP study of the effect of alpha-tocopherol alone, no reduction in disease progression was seen. The problem with this study was the low dose that was used and the fact that the DL-alpha-tocopherol used is known to have a much lower antioxidant potency than D-alpha-tocopherol. Stanley Fahn found that a combination of D-alpha-tocopherol and ascorbic acid in high doses reduced progression of the disease by 2.5 years.39 Tocotrienol may have even greater benefits, especially when used in combination with other antioxidants. There is some clinical evidence, including my own observations, that vitamin E also slows the course of ALS as well, especially in the form of D- alpha-tocopherol. I would caution that antioxidants work best in combination and when use separately can have opposite, harmful, effects. That is, when antioxidants, such as ascorbic acid and alpha tocopherol, become oxidized themselves, such as in the case of dehydroascorbic acid, they no longer protect, but rather act as free radicals themselves. The same is true of alpha-tocopherol.40
Again, it should be realized that excessive glutamate stimulation triggers a chain of events that in turn sparks the generation of large numbers of free radical species, both as nitrogen and oxygen species. These free radicals have been shown to damage cellular proteins ( protein carbonyl products) and DNA . The most immediate DNA damage is to the mitochondrial DNA, which controls protein expression within that particular cell and its progeny, producing rather profound changes in cellular energy production. It is suspected that at least some of the neurodegenerative diseases, Parkinson's disease in particular, are affected in this way.41 Chronic free radical accumulation would result in an impaired functional reserve of antioxidant vitamins/minerals and enzymes, and thiol compounds necessary for neural protection. Chronic unrelieved stress, chronic infection, free radical generating metals and toxins, and impaired DNA repair enzymes all add to this damage.
We know that there are four main endogenous sources of oxidants:
1. Those produced naturally from aerobic metabolism of glucose.
2. Those produced during phagocytic cell attack on bacteria, viruses, and parasites, especially with chronic infections.
3. Those produced during the degradation of fatty acids and other molecules that produce h3O2 as a by-product. (This is important in stress, which has been shown to significantly increase brain levels of free radicals.) And
4. Oxidants produced during the course of p450 degradation of natural toxins. And, as we have seen, one of the major endogenous sources of free radicals is from the exposure of tissues to free iron, especially in the presence of ascorbate. Unfortunately, iron is one mineral heavily promoted by the health industry, and is frequently added to many foods, especially breads and pastas. Copper is also a powerful free radical generator and has been shown to be elevated within the substantia nigra of Parkinsonian brains.42
What has been shown in all these studies is a direct connection between excitotoxicity and free radical generation in a multitude of diseases and disorders such as seizures, strokes, brain trauma,viral infections, and neurodegenerative diseases. Interestingly, free radicals have also been shown to prevent glutamate uptake by astrocytes as well, which would significantly increase extracellular glutamate levels.43 This creates a vicious cycle that will multiply any resulting damage and malfunctioning of neurophysiological systems, such as plasticity.
