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.
Showing posts with label neurodegenerative diseases. Show all posts
Showing posts with label neurodegenerative diseases. Show all posts
Thursday, August 21, 2008
Thursday, July 31, 2008
Part 4 Excitotoxins, Neurodegeneration and Neurodevelopment
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.
.
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.
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