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.
Thursday, August 21, 2008
Thursday, August 14, 2008
Part 6 Excitotoxins, Neurodegeneration and Neurodevelopment
Excitotoxins, Neurodegeneration and Neurodevelopment
By Russell L. Blaylock, M.D
Relation to Cellular Energy Production
Excitotoxin damage is heavily dependent on the energy state of the cell.49 Cells with a normal energy generation systems are very resistant to such toxicity. When cells are energy deficient, no matter the cause - hypoxia, starvation, metabolic poisons, hypoglycemia - they become infinitely more susceptible to excitotoxic injury or death. Even normal concentrations of glutamate are toxic to energy deficient cells.
It is known that in many of the neurodegenerative disorders, neuron energy deficiency often precedes the clinical onset of the disease by years, if not decades.50 This has been demonstrated in the case of Huntington disease and Alzheimer's disease using the PET scanner, which measures brain metabolism. In the case of Parkinson's disease, several groups have demonstrated that one of the early deficits of the disorder is an impaired energy production by the complex I group of enzymes within the mitochondria of the substantia nigra.51-52Interestingly, it is known that the complex I system is very sensitive to free radical damage.
Recently, it has been shown that when striatal neurons are exposed to microinjected excitotoxins there is a dramatic, and rapid fall in energy production by these neurons. CoEnzyme Q10 has been shown, in this model, to restore energy production but not to prevent cellular death. But when combined with niacinamide, both cellular energy production and neuron protection is seen.53 I recommend for those with neurodegenerative disorders, a combination of CoQ10, acetyl-L carnitine, niacinamide, riboflavin, methylcobalamin, and thiamine.
One of the newer revelation of modern molecular biology, is the discovery of mitochondrial diseases, of which cellular energy deficiency is a hallmark. In many of these disorders, significant clinical improvement has been seen following a similar regimen of vitamins combined with CoQ10 and L-carnitine.54 Acetyl L-carnitine enters the brain in higher concentrations and also increases brain acetylcholine, necessary for normal memory function. While these particular substances have been found to significantly boost brain energy function they are not alone in this important property. Phosphotidyl serine, Ginkgo Biloba, vitamin B12, folate, magnesium, Vitamin K and several others are also being shown to be important.
While mitochrondial dysfunction is important in explaining why some are more vulnerable to excitotoxin damage than others, it does not explain injury in those with normal cellular metabolism. There are several conditions under which energy metabolism is impaired. We know, for example, approximately one third of Americans suffer from reactive hypoglycemia. That is, they respond to a meal composed of either simple sugars or carbohydrates (that are quickly broken down into simple sugars, i.e. a high glycemic index.) by secreting excessive amounts of insulin. This causes a dramatic lowering of the blood sugar.
When the blood sugar falls, the body responds by releasing a burst of epinephrine from the adrenal glands, in an effort to raise the blood sugar. We feel this release as nervousness, palpitations of our heart, tremulousness, and profuse sweating. Occasionally, one can have a slower fall in the blood sugar that will not produce a reactive release of epinephrine, thereby producing few symptoms. This can be more dangerous, since we are unaware that our glucose reserve is falling until we develop obvious neurological symptoms, such as difficulty thinking and a sensation of lightheadedness.
The brain is one of the most glucose dependent organs known, since it has a limited ability to metabolize other substrates such as fats. There is some evidence that several of the neurodegenerative diseases are related to either excessive insulin release, as with Alzheimer's disease, or impaired glucose utilization, as we have seen in the case of Parkinson's disease and Huntington's disease.55
It is my firm belief, based on clinical experience and physiological principles, that many of these diseases occur primarily in the face of either reactive hypoglycemia or " brain hypoglycemia", a condition where the blood sugar is normal and the brain is hypoglycemic in isolation. In at least two well conducted studies it was found that pure Alzheimer's dementia was rare in those with normal blood sugar profiles, and that in most cases Alzheimer's patients had low blood sugars, and high CSF ( cerebrospinal fluid) insulin levels.55-57 In my own limited experience with Parkinson's and ALS patients I have found a disproportionately high number suffering from reactive hypoglycemia.
I found it interesting that several ALS patients have observed an association between their symptoms and gluten. That is, when they adhere to a gluten free diet they improve clinically. It may be that by avoiding gluten containing products, such as bread, crackers, cereal, pasta ,etc, they are also avoiding products that are high on the glycemic index, i.e. that produce reactive hypoglycemia. Also, all of these food items are high in free iron. Clinically, hypoglycemia will worsen the symptoms of most neurological disorders. We know that severe hypoglycemia can, in fact, mimic ALS both clinically and pathologically.58 It is also known that many of the symptoms of Alzheimer's disease resemble hypoglycemia, as if the brain is hypoglycemic in isolation.
In studies of animals exposed to repeated mild episodes of hypoxia ( lack of brain oxygenation), it was found that such accumulated injuries can trigger biochemical changes that resemble those seen in Alzheimer's patients.59 One of the effects of hypoxia is a massive release of glutamate into the space around the neuron. This results in rapid death of these sensitized cells. As we age, the blood supply to the brain is frequently impaired, either because of atherosclerosis or repeated syncopal episodes, leading to short periods of hypoxia. Hypoglycemia produces lesions very similar to hypoxia and via the same glutamate excitotoxic mechanism. In fact, recent studies of diabetics suffering from repeated episodes of hypoglycemia associated with over medication with insulin, demonstrate brain atrophy and dementia.60
Another cause of isolated cerebral hypoglycemia is impaired transport of glucose into the brain across the blood-brain barrier. It is known that glucose enters the brain by way of a glucose transporter, and that in several conditions this transporter is impaired. This includes aging, arteriosclerosis, and Alzheimer's disease.61-62 This is especially important in the diabetic since prolonged elevation of the blood sugar produces a down-regulation of the glucose transporter and a concomitant " brain hypoglycemia" that is exacerbated by repeated spells of peripheral hypoglycemia common to type I diabetics.
With aging, one sees several of these energy deficiency syndromes, such as mitochondrial injury, impaired cerebral blood flow, enzyme dysfunction, and impaired glucose transportation, develop simutaneously. This greatly magnifies excitotoxicity, leading to accelerated free radical injury and a progressively rapid loss of cerebral function and profound changes in cellular energy production.63 It is suspected that at least in some of the neurodegenerative diseases, Alzheimer's dementia and Parkinson's disease in particular, this series of events plays a major pathogenic role.64 Chronic free radical accumulation would also result in an impaired functional reserve of antioxidant vitamins/minerals, antioxidant enzymes (SOD, catalase, and glutathione peroxidase), 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.
It is estimated that the number of oxidative free radical injuries to DNA number about 10,000 a day in humans.65 Under conditions of cellular stress this may reach several hundred thousand.Normally, these injuries are repaired by special DNA repair enzymes. It is known that as we age these repair enzymes decrease or become less efficient.66 Also, some individuals are born with deficient repair enzymes from birth as, for example, in the case of xeroderma pigmentosum. Recent studies of Alzheimer's patients also demonstrate a significant deficiency in DNA repair enzymes and high levels of lipid peroxidation products in the affected parts of the brain.67-68 It is also important to realize that the hippocampus of the brain, most severely damaged in Alzheimer's dementia, is one of the most vulnerable areas of the brain to low glucose supply as well as low oxygen supply. That also makes it very susceptible to glutamate/ free radical toxicity.
Another interesting finding is that when cells are exposed to glutamate they develop certain inclusions ( cellular debris) that not only resembles the characteristic neurofibrillary tangles of Alzheimer's dementia, but are immunologically identical as well.69 Similarly, when experimental animals are exposed to the chemical MPTP, they not only develop Parkinson's disorder, but the older animals develop the same inclusions ( Lewy bodies) as see in human Parkinson's.70 There is growing evidence that protracted glutamate toxicity leads to a condition of receptor loss characteristic of neurodegeneration.71 This receptor loss produces a state of disinhibition that magnifies excitotoxicity during the later stage of the neurodegenerative process.
By Russell L. Blaylock, M.D
Relation to Cellular Energy Production
Excitotoxin damage is heavily dependent on the energy state of the cell.49 Cells with a normal energy generation systems are very resistant to such toxicity. When cells are energy deficient, no matter the cause - hypoxia, starvation, metabolic poisons, hypoglycemia - they become infinitely more susceptible to excitotoxic injury or death. Even normal concentrations of glutamate are toxic to energy deficient cells.
It is known that in many of the neurodegenerative disorders, neuron energy deficiency often precedes the clinical onset of the disease by years, if not decades.50 This has been demonstrated in the case of Huntington disease and Alzheimer's disease using the PET scanner, which measures brain metabolism. In the case of Parkinson's disease, several groups have demonstrated that one of the early deficits of the disorder is an impaired energy production by the complex I group of enzymes within the mitochondria of the substantia nigra.51-52Interestingly, it is known that the complex I system is very sensitive to free radical damage.
Recently, it has been shown that when striatal neurons are exposed to microinjected excitotoxins there is a dramatic, and rapid fall in energy production by these neurons. CoEnzyme Q10 has been shown, in this model, to restore energy production but not to prevent cellular death. But when combined with niacinamide, both cellular energy production and neuron protection is seen.53 I recommend for those with neurodegenerative disorders, a combination of CoQ10, acetyl-L carnitine, niacinamide, riboflavin, methylcobalamin, and thiamine.
One of the newer revelation of modern molecular biology, is the discovery of mitochondrial diseases, of which cellular energy deficiency is a hallmark. In many of these disorders, significant clinical improvement has been seen following a similar regimen of vitamins combined with CoQ10 and L-carnitine.54 Acetyl L-carnitine enters the brain in higher concentrations and also increases brain acetylcholine, necessary for normal memory function. While these particular substances have been found to significantly boost brain energy function they are not alone in this important property. Phosphotidyl serine, Ginkgo Biloba, vitamin B12, folate, magnesium, Vitamin K and several others are also being shown to be important.
While mitochrondial dysfunction is important in explaining why some are more vulnerable to excitotoxin damage than others, it does not explain injury in those with normal cellular metabolism. There are several conditions under which energy metabolism is impaired. We know, for example, approximately one third of Americans suffer from reactive hypoglycemia. That is, they respond to a meal composed of either simple sugars or carbohydrates (that are quickly broken down into simple sugars, i.e. a high glycemic index.) by secreting excessive amounts of insulin. This causes a dramatic lowering of the blood sugar.
When the blood sugar falls, the body responds by releasing a burst of epinephrine from the adrenal glands, in an effort to raise the blood sugar. We feel this release as nervousness, palpitations of our heart, tremulousness, and profuse sweating. Occasionally, one can have a slower fall in the blood sugar that will not produce a reactive release of epinephrine, thereby producing few symptoms. This can be more dangerous, since we are unaware that our glucose reserve is falling until we develop obvious neurological symptoms, such as difficulty thinking and a sensation of lightheadedness.
The brain is one of the most glucose dependent organs known, since it has a limited ability to metabolize other substrates such as fats. There is some evidence that several of the neurodegenerative diseases are related to either excessive insulin release, as with Alzheimer's disease, or impaired glucose utilization, as we have seen in the case of Parkinson's disease and Huntington's disease.55
It is my firm belief, based on clinical experience and physiological principles, that many of these diseases occur primarily in the face of either reactive hypoglycemia or " brain hypoglycemia", a condition where the blood sugar is normal and the brain is hypoglycemic in isolation. In at least two well conducted studies it was found that pure Alzheimer's dementia was rare in those with normal blood sugar profiles, and that in most cases Alzheimer's patients had low blood sugars, and high CSF ( cerebrospinal fluid) insulin levels.55-57 In my own limited experience with Parkinson's and ALS patients I have found a disproportionately high number suffering from reactive hypoglycemia.
I found it interesting that several ALS patients have observed an association between their symptoms and gluten. That is, when they adhere to a gluten free diet they improve clinically. It may be that by avoiding gluten containing products, such as bread, crackers, cereal, pasta ,etc, they are also avoiding products that are high on the glycemic index, i.e. that produce reactive hypoglycemia. Also, all of these food items are high in free iron. Clinically, hypoglycemia will worsen the symptoms of most neurological disorders. We know that severe hypoglycemia can, in fact, mimic ALS both clinically and pathologically.58 It is also known that many of the symptoms of Alzheimer's disease resemble hypoglycemia, as if the brain is hypoglycemic in isolation.
In studies of animals exposed to repeated mild episodes of hypoxia ( lack of brain oxygenation), it was found that such accumulated injuries can trigger biochemical changes that resemble those seen in Alzheimer's patients.59 One of the effects of hypoxia is a massive release of glutamate into the space around the neuron. This results in rapid death of these sensitized cells. As we age, the blood supply to the brain is frequently impaired, either because of atherosclerosis or repeated syncopal episodes, leading to short periods of hypoxia. Hypoglycemia produces lesions very similar to hypoxia and via the same glutamate excitotoxic mechanism. In fact, recent studies of diabetics suffering from repeated episodes of hypoglycemia associated with over medication with insulin, demonstrate brain atrophy and dementia.60
Another cause of isolated cerebral hypoglycemia is impaired transport of glucose into the brain across the blood-brain barrier. It is known that glucose enters the brain by way of a glucose transporter, and that in several conditions this transporter is impaired. This includes aging, arteriosclerosis, and Alzheimer's disease.61-62 This is especially important in the diabetic since prolonged elevation of the blood sugar produces a down-regulation of the glucose transporter and a concomitant " brain hypoglycemia" that is exacerbated by repeated spells of peripheral hypoglycemia common to type I diabetics.
With aging, one sees several of these energy deficiency syndromes, such as mitochondrial injury, impaired cerebral blood flow, enzyme dysfunction, and impaired glucose transportation, develop simutaneously. This greatly magnifies excitotoxicity, leading to accelerated free radical injury and a progressively rapid loss of cerebral function and profound changes in cellular energy production.63 It is suspected that at least in some of the neurodegenerative diseases, Alzheimer's dementia and Parkinson's disease in particular, this series of events plays a major pathogenic role.64 Chronic free radical accumulation would also result in an impaired functional reserve of antioxidant vitamins/minerals, antioxidant enzymes (SOD, catalase, and glutathione peroxidase), 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.
It is estimated that the number of oxidative free radical injuries to DNA number about 10,000 a day in humans.65 Under conditions of cellular stress this may reach several hundred thousand.Normally, these injuries are repaired by special DNA repair enzymes. It is known that as we age these repair enzymes decrease or become less efficient.66 Also, some individuals are born with deficient repair enzymes from birth as, for example, in the case of xeroderma pigmentosum. Recent studies of Alzheimer's patients also demonstrate a significant deficiency in DNA repair enzymes and high levels of lipid peroxidation products in the affected parts of the brain.67-68 It is also important to realize that the hippocampus of the brain, most severely damaged in Alzheimer's dementia, is one of the most vulnerable areas of the brain to low glucose supply as well as low oxygen supply. That also makes it very susceptible to glutamate/ free radical toxicity.
Another interesting finding is that when cells are exposed to glutamate they develop certain inclusions ( cellular debris) that not only resembles the characteristic neurofibrillary tangles of Alzheimer's dementia, but are immunologically identical as well.69 Similarly, when experimental animals are exposed to the chemical MPTP, they not only develop Parkinson's disorder, but the older animals develop the same inclusions ( Lewy bodies) as see in human Parkinson's.70 There is growing evidence that protracted glutamate toxicity leads to a condition of receptor loss characteristic of neurodegeneration.71 This receptor loss produces a state of disinhibition that magnifies excitotoxicity during the later stage of the neurodegenerative process.
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