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09-02-2007, 10:55 PM | #1 | |||
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In Remembrance
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with much love, lou_lou . . by . , on Flickr pd documentary - part 2 and 3 . . Resolve to be tender with the young, compassionate with the aged, sympathetic with the striving, and tolerant with the weak and the wrong. Sometime in your life you will have been all of these. Last edited by lou_lou; 09-02-2007 at 11:45 PM. Reason: poor title sp? |
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09-02-2007, 11:04 PM | #2 | |||
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In Remembrance
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Nutraceuticals and Metabolic Stimulants
Russell L. Blaylock, MD* [B]Board Certified Neurosurgeon, Clinical Assistant Professor University of Mississippi Medical Center, Jackson, Mississippi Winter 2002[/B ]INTRODUCTION Neurodegeneration was once considered to be a simple acceleration of the normal aging process. Aging of the brain, however, generally produces little deterioration of neurological function. Neurodegeneration on the other hand, results in an appreciable loss of cognitive and motor function. Hence, a significant loss of cognitive ability is always pathological. In this review I will discuss several changes that occur with neurodegeneration and offer potential ways to reduce one’s risk of developing a neurodegenerative disorder. THE CENTRAL MECHANISM OF NEURODEGENERATION When one reviews the extensive literature on neurodegeneration, one finds many seemingly unrelated pathological events, such as excitotoxicity, viral inflammation, autoimmune reactions, trauma, cerebrovascular impairment, and metal toxicity. Surprisingly, a single central mechanism explains all.1 This mechanism is a combination of excitotoxic injury coupled with free radical damage to neural tissue. Excitotoxins are neurotransmitters, such as glutamate or aspartate, that can cause cell death when their actions are prolonged. These chemicals are thought to play and important role in ischemic brain damage. A free radical molecule has an unpaired electron in its outer orbital, one that robs surrounding molecules of their electrons, generating a process referred to as oxidation or oxidative stress. The particles responsible for this oxidative injury are referred to as reactive oxygen species (ROS). A related particle, discussed less often in the lay literature, is the reactive nitrogen species (RNS). Its nitrogen atom interacts chiefly with amino acids, such as tyrosine, interfering with numerous biochemical processes in the central nervous system. When these particles react with tyrosine they form nitrotyrosine, a measurable marker for RNS damage. As we shall see, these oxygen and nitrogen products are commonly found in the tissues of those with neurodegenerative disorders, such as Alzheimer’s dementia, Parkinson’s disease, Huntington’s disease and Lou Gehrig’s disease (ALS). The excitotoxic process entails a complicated series of reactions involving the release of the amino acid neurotransmitter glutamate. Glutamate reacts at a series of receptors on the neuron’s surface that in turn, either directly or indirectly, control the calcium pore or channel.2 This channel tightly regulates the entry of calcium into the neuron. Calcium homeostasis is critical because its loss is the trigger for numerous abnormal signaling systems in the neuron, which when over-stimulated can precipitate the destructive generation of free radicals and inflammatory reactions that can ultimately lead to the death of the cell. For this reason, glutamate levels outside the neuron are carefully regulated. Even small elevations in glutamate can precipitate the destructive reactions we refer to as excitotoxicity. Glutamate content outside the neuron is controlled by a re-uptake system that involves a series of glutamate transport proteins.3 Should too much calcium enter the neuron, other cellular mechanisms act to remove it, either by moving it into the mitochondria, pumping it outside the neuron, or sequestering it in the endoplasmic reticulum.4 All of these processes require cellular energy. When cellular energy supplies fall, these protective systems fail. Calcium acts as a biochemical trigger for numerous reactions, all of which play a vital role in neuron function, such as nitric oxide signaling information, activation of special eicosanoids and regulation of the neuron’s gene messages.5 When too much calcium enters the cell, it triggers an excessive production of nitric oxide, a cell-signaling molecule.6 As the nitric oxide begins to build up, it interacts with the superoxide radical to produce the highly reactive and destructive peroxynitrite radical. This radical wreaks havoc on the mitochondria, producing injury to its enzymes (electron transport chain) and in addition, damages mitochondrial DNA.7 A significant loss of cellular energy production results. Excess calcium also stimulates the activation of the enzyme protein kinase C, which activates the membranebound enzyme, phospholipase A2 ( PLA2).8 This enzyme in turn releases arachidonic acid from the membrane lipid stores, where it is then acted upon by two enzymes, cyclooxygenase (COX) and lipoxygenase (LOX), which convert it into numerous reactive molecules called prostaglandins and leukotrienes. Both metabolic products, when present in excess, can drastically increase free radical production.9 As the level of free radicals begin to rise, they interact with the lipids in the cell’s various membranes, setting up a chain reaction called lipid peroxidation. The peroxyl radical plays a major role in membrane injury as well as injury to mitochondria.10 As the destructive process spreads through the membrane, secondary metabolic products are produced, such as 4-hydroxynonenal, which can be even more destructive.11 Cellular proteins are building blocks for the hundreds of enzymes used by each cell to function. Free radicals interact with both proteins and carbohydrates in the cell, causing conformational changes in their structure. While free-radical- altered proteins, called carbonyl products, increase with aging, they don’t increase to the extent we see in the tissues of those with neurodegenerative diseases.12,13 Another cell component damaged by free radicals is DNA. The cell contains two sets of DNA: one type in the nucleus, and another in each of the cell’s numerous mitochondrion. Mitochondrial DNA is especially vulnerable to oxidation reactions, being about 10X more sensitive to free radical damage.14 * Correspondence: Russell L. Blaylock, MD 315 Rolling Meadows Ridgeland, Mississippi 39157 Phone: 601-982-1175 E-mail: dodd@netdoor.com
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with much love, lou_lou . . by . , on Flickr pd documentary - part 2 and 3 . . Resolve to be tender with the young, compassionate with the aged, sympathetic with the striving, and tolerant with the weak and the wrong. Sometime in your life you will have been all of these. |
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09-02-2007, 11:13 PM | #3 | |||
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In Remembrance
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This is important because with aging,
oxidized DNA begins to accumulate, resulting in dwindling cell energy supplies.15 Cellular low energy causes reduced function of the neurons and increased sensitivity to excitotoxicity. The susceptibility of mitochondrial DNA to free radical oxidation increases with age, being 15X more active after age 70. As this process accelerates, a special autodestructive gene, called the p53 gene, is activated.16 Its purpose is to kill the neuron when the cell is so badly damaged that it cannot be restored to health by the cell’s reparative enzymes. Much of the destructive change seen in neurodegenerative disorders, at least in the earlier stages, does not entail neuron death. Several studies have shown that in the case of Alzheimer’s disease, most of the damage is directed at the neuron processes, such as the dendrites and synapses.17 While we do not completely understand the role played by ß-amyloid peptides, we do know that much of their destructive potential comes from the free-radical-generating molecule hydrogen peroxide.18 Amyloid has also been shown to enhance excitotoxicity.19 Another pathological characteristic of Alzheimer’s disease is the presence of microscopic neurofibrillary tangles composed of over-phosphorylated tau protein. Recent evidence has demonstrated that the lipid peroxidation product 4-hydroxynonenal interacts with the tau protein to accelerate this process, and prevents the tau proteins from dephosphorylating. 20 Several of the transition metals such as aluminum and mercury, and exposure to MSG can precipitate the same event experimentally.21Finally, the entire process involves an overreacting immune system apparently triggered by excitotoxicity and free radical injury.22 The microglial cell, the cellular basis of central nervous system immunity, is activated by any event that increases the free radical-excitotoxicity cascade. 23 As we shall see, CNS immune activation plays a major role in neurodegeneration. This entire process appears to be the same for numerous conditions including autoimmune diseases, viral encephalitis, Lyme disease, AIDS dementia syndrome, brain injury, strokes, heavy metal toxicity, spongioform encephalitis (Mad Cow disease), and most of the degenerative brain disorders, such as Alzheimer’s dementia, Parkinson’s disease, Huntington’s disease, and ALS. IRON AND NEURODEGENERATION It is known that as we age our brain accumulates more free iron.24 In the past it was assumed that only free iron was harmful; recent evidence indicates that even iron combined to ferritin can damage neurons.25 Excessive iron accumulation is seen in many neurodegenerative disorders, including Alzheimer’s dementia, Parkinson’s disease, and ALS. In biological systems, iron is known as one of the most powerful free radical generators.
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with much love, lou_lou . . by . , on Flickr pd documentary - part 2 and 3 . . Resolve to be tender with the young, compassionate with the aged, sympathetic with the striving, and tolerant with the weak and the wrong. Sometime in your life you will have been all of these. |
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09-02-2007, 11:17 PM | #4 | |||
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In Remembrance
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Recent evidence indicates that those at risk of developing
Parkinson’s disease have a defect in iron metabolism.26 In this study, Parkinson patients’ total iron binding capacity and transferritin saturation were significantly lower than that of controls, with no difference in their dietary intake of iron. Other researchers have found increased iron and aluminum in the neuromelanin pigment in the substantia nigra of Parkinson’s patients.27 Aluminum appears to displace iron from the ferritin molecule, thereby increasing the interaction of iron during the hydrogen peroxide interaction with superoxide. This reaction forms the powerful hydroxyl radical. 28 In the brains of Alzheimer’s disease patients, aluminum, iron, and mercury are consistently found in elevated concentrations in affected neurons,29 transferritin levels are decreased, and iron, ferritin, and transferritin are concentrated around the senile plaques. ALUMINUM AND NEURODEGENERATION The connection between aluminum exposure and brain dysfunction was strengthened when several dialysis units reported patients with an unusual dementing syndrome related to elevated aluminum levels in the dialyslate.30 Once the dialysis water was cleared of aluminum, the dementing syndrome disappeared. Based on this finding, others began to suspect aluminum toxicity as an etiology of Alzheimer’s disease. One early study, in which individuals were examined in 88 counties in England and Wales, areas with elevated aluminum levels in the drinking water had higher incidences of Alzheimer’s dementia.31 A later, more well-controlled study found that elderly people who drank water high in aluminum had a 4.4X higher incidence of Alzheimer’s disease than those who drank water with lower levels.32 After this suggestive research, more accurate studies were conducted for measuring brain levels of aluminum in several neurodegenerative disorders. Despite early conflicting results, the latest studies performed with microtechnique high-tech laser and x-ray probes clearly indicate elevated levels of aluminum in the area of neurofibrillary tangles in Alzheimer’s disease.33 Similar results have been found in cases of Parkinson’s disease.34 The results of one ALS study indicated that while spinal cord levels of aluminum were not elevated above controls, they did find a 1.5- to 2-fold elevation in iron and calcium.35 Using more sophisticated methods, another study confirmed the earlier finding of elevated aluminum levels in the motor neurons of ALS patients.36 Besides increasing free radical generation, aluminum has several other negative effects on cell function. One study found that primates exposed to excess aluminum had a significant decrease in total lipid, glycolipid, and phospholipid content in their brains.37 Aluminum also damages membrane-bound enzymes such as Na+-K+ATPase, acetylcholinesterase, and 2’, 3’-cyclic nucleotide phosphohydrolase, all enzymes necessary for normal neuron function. A recent study found that aluminum in the presence of melanin significantly enhanced lipid peroxidation.38 This is important in the case of Parkinson’s disease, since the neuromelanin- containing cells of the substantia nigra are the cells most affected by the disease. Of enormous importance is the finding that high aluminum levels can inhibit the activity of many antioxidant enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase.39 Several studies have linked aluminum to formation of the paired helical filaments found in Alzheimer’s disease.40 Aluminum appears to interfere with dephosphorylation of the hyperphosphorylated tau protein. Experimentally, using the aluminum-chelating agent desferrioxamine, researchers could reverse this resistance to aluminum-induced dephosphorylation. 41 The entry of aluminum into the brain, past the bloodbrain barrier, is significantly enhanced when aluminum is bound to glutamate.42 Once in the brain, aluminum has been shown to potentate excitotoxicity by enhancing glutamate- triggered calcium accumulation within the neuron,43 and to increase the formation of iron-induced free radicals. Is aluminum the only cause of these neurodegenerative diseases? I don’t think so. However, I do think that it is a significant contributing factor. Numerous environmental agents, viruses, autoimmune disorders, and injuries can all trigger the same central destructive mechanism—excitotoxicity. Often we see several of these factors coexisting in the same person. At high risk is the person having mineral deficiencies, poor nutritional supply of antioxidants, and antioxidant enzyme deficiencies. It is interesting to note that gastrointestinal absorption of aluminum was found to be enhanced in Down’s syndrome, a condition with pathological features similar to Alzheimer’s disease.44 In this study, aluminum absorption in Down’s syndrome was 4X greater when absorbed as an antacid, and 6X higher in the presence of citrate than that seen in controls. Another study found that adding citrate to aluminum hydroxide antacid increased absorption as much as 11X in normal adults.45 This may be a good reason to not add lemon juice to your tea, since tea is high in aluminum and lemons are high in citrate. A monocarboxylic acid transporter controls entry of aluminum into the brain. Pyruvate competes with aluminum citrate for entry, thereby providing a way to inhibit brain accumulation of aluminum.46 Pyruvate, as well as malate, have also been shown to inhibit glutamate toxicity.47 INFLAMMATION, CYTOKINES AND AUTOIMMUNITY For many years scientists suspected that the immune
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with much love, lou_lou . . by . , on Flickr pd documentary - part 2 and 3 . . Resolve to be tender with the young, compassionate with the aged, sympathetic with the striving, and tolerant with the weak and the wrong. Sometime in your life you will have been all of these. |
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09-02-2007, 11:23 PM | #5 | |||
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In Remembrance
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system played an important role in neurodegeneration. It is
known that with aging we begin to develop immune complexes to brain components.48 Some have proposed that this is the function of immune suppression commonly seen with aging, to reduce the immune attack. Studies of Alzheimer’s patients have shown elevated cytokines IL-1ß, IL-2, IL-6, S-100 protein, tumor necrosis factor alpha (TNF-alpha), and significant isolated autoantibodies to GM1.49,50 One also sees elevated levels of PGD2 and thromboxane B2, both inflammatory cytokines, in Alzheimer’s disease.51 Autoantibodies have also been described in amyotrophic lateral sclerosis as well.52 This immune attack on neurons produces a state of chronic inflammation that generates a constant high level of free radicals.53 As the damage continues, the p53 gene is activated, leading to apoptosis.54 Short of actual destruction of the neurons, a reduction in mitochondrial energy generation leads to increased free radical production. In addition, low energy levels make the neurons infinitely more sensitive to the excitotoxic effects of glutamate and aspartate. 55,56 In fact, in the face of low energy production, even normal levels of glutamate can kill neurons. Glutamate, in turn, stimulates the microglia, the CNS immune cell, to produce even more cytokines, and to release the two excitotoxins glutamate and quinolinic acid.57 This viscous cycle leads to eventual neuronal cell death. As we see, glutamate itself can act as the trigger for microglial activation leading to the release of numerous inflammatory cytokines, or some other event may trigger the process, such as a viral infection, Lyme disease organism invasion, or even heavy metal exposure. One factor that may lead to autoimmunity is the prolonged assault of the brain’s cellular components to oxidative stress. Oxidation of the proteins, which alters their structure, can lead to autoimmunity. Recent studies have shown that activation of the transcription factor NF kappa B plays a major role in neurodegeneration. This transcription factor stimulates the production of various cytokines including IL-1ß, IL-2, IL-6 and TNF-alpha, all of which are increased in neurodegenerative diseases.58,59,60 Oxidative stress is a common trigger for NF kappa B activation. Beta-amyloid has been shown to activate microglia by way of protein kinase C.61 Studies indicate that beta-amyloid production is increased in the face of activated microglia and that the presence of beta-amyloid is sufficient to maintain chronic brain inflammation. Microglia themselves contain enough glutamate to elicit excitotoxicity. They can also precipitate excitotoxicity by stimulating the release of arachidonic acid.62 Microglia also contain considerable amounts of the excitotoxin quinolinic acid, which can be released during activation.63 Quinolenic acid is a metabolic product of serotonin metabolism. Animal studies have shown that mice with autoimmune disorders have a more rapid decline in aged-related learning than normal animals.64 ADVANCED GLYCATION END PRODUCTS One of the consequences of a high dietary intake of glucose, and especially fructose, is the glycation of numerous proteins in the cell.65 When proteins are glycated, that is, combined with sugar molecules, they become significantly more vulnerable to free radical damage and produce advance glycation end products (AGEs) which can interfere with tyrosine and dopa utilization. Elevated levels of AGEs have been found in Alzheimer’s, Parkinson’s disease, and ALS.66,67 This is especially so in Parkinson’s disease because of the early fall in cellular glutathione levels. The problem of large amounts of AGEs is that they signal glia cells to produce superoxide and nitric oxide,68 a combination that leads to the production of the powerful peroxynitrite radical. Cytokines are also potent stimulators of inducible nitric oxide, and hence peroxynitrite production. PEROXYNITRITE As stated, when nitric oxide combines with superoxide it produces peroxynitrite. This free radical is unusual in that it is resistant to most of the common antioxidants, such as vitamin C, vitamin E and the carotenoids.69 The most powerful scavenger of peroxynitrite is glutathione. When glutathione levels are low, as is seen in Parkinson’s disease as well as Alzheimer’s dementia and ALS, neurons become significantly more vulnerable. Peroxynitrite tends to concentrate in the mitochondria, where it damages enzymes as well as DNA.70 These events dramatically interfere with the cell’s ability to produce energy. Neurons and glia are very energy dependent. Virtually every cellular process requires enormous amounts of energy. The brain consumes 20% of the blood’s oxygen and 25% of its glucose, even though it constitutes only 2% of body weight. Even under deep anesthesia, the brain’s metabolism is reduced only 50%.71 Several studies have demonstrated elevated peroxynitrite levels in Alzheimer’s disease, ALS and Parkinson’s disease.72 Damage by peroxynitrite is indicated by the accumulation of nitrotyrosine. 4-HYDROXYNONENAL (4-HNE) 4-hydroxynonenal (4-HNE) is an aldehydic product of lipid peroxidation. While malondialdhyde (MDA) is the most abundant product of lipid peroxidation, 4-hydroxynonenal is the most reactive with proteins. Interestingly, the distribution of damage by peroxynitrite parallels that of 4-HNE.73 There is growing evidence that 4-HNE plays a major role in several neurodegenerative disorders, including 19 JANA Vol. 5, No. 1 Winter 2002 Alzheimer’s dementia, Parkinson’s disease and ALS. In one study of seven Alzheimer’s disease patients, 4-HNE was found to be associated with all amyloid deposits and most perivascular areas (89%).74 Another study found increased 4-HNE in several areas of the brain in Alzheimer’s disease, reaching significant levels in the amygdala, hippocampus and parahippocampus, areas of primary damage in the disorder.75 Elevations of 4- HNE have also been found in the ventricular fluid of Alzheimer’s patients but not in age-matched controls.76 The distribution of 4-HNE appears to be dependent on the presence of the APOE genotype. APOE4-possessing subjects demonstrated primary accumulation of 4-HNE in the cytoplasm of pyramidal neurons, while APOE3 genotypes had both astrocytic and pyramidal cell distribution.77 APOE4 is strongly associated with Alzheimer’s disease as well as a high risk of dementia pugilistica in boxers.78 It is also known that individuals with APOE4 genotype have impaired antioxidant enzymes, which may be the basis of their increased incidence of neurodegenerative diseases.79 Injecting 4-HNE into the brain of rats causes a widespread loss of neurons in the basal forebrain ipsilateral to the injection and a 60 to 80% reduction in choline acetyltransferase seven days post-injection.80 When FeCl2 is given, it increases the levels of 4-HNE in the brain. Similar elevation of 4-HNE has been demonstrated in Parkinson’s disease.81 A study of seven brains of Parkinson’s disease patients, demonstrated immunostaining for 4-HNE in the striatum, but demonstrated the same findings in only 9% of aged-matched controls. Direct injection of 4-HNE into the substantia nigra of mice caused a dose-dependent depletion of glutathione in the brainstem.82 Glutathione levels fall early in Parkinson’s disease. 4-HNE has also been shown to rapidly inactivate glutathione reductase, needed to convert oxidized glutathione to its reduced form.83 One of the best correlations with cognitive function in Alzheimer’s disease is the synaptic concentration in the brain.84 4-HNE has been shown to conjugate to synaptic proteins and to impair transport of both glucose and glutamate. Both result in a significant decrease in cellular production of ATP.85 HOMOCYSTEINE AND OXIDIZED CHOLESTEROL While the cardiovascular system has gotten most of the attention as regards homocysteine and cholesterol, the nervous system is also vulnerable to its effects. Both LDL and HDL exist in the brain, with LDL acting as a transporter of cholesterol and phospholipids in the CNS. Receptors for LDL have been located on microvessels, astrocytes, microglia, and neurons.86 Like LDL in the plasma, brain LDL and HDL can become oxidized, especially in the presence of increased catalytic iron.87 It has been shown that oxidized LDL in the striatum enters the neuron and can induce cell death. The mechanism of neuronal injury is closely connected to excitotoxicity since glutamate-blocking drugs, such as MK-801, protect the neuron from oxidized LDL-mediated cell death.88 Highly oxidized HDL in the brain has also been shown to increase oxidative stress in astrocytes, microglia, and neurons, causing death in the latter.89 When oxidized lipoproteins exist in the presence of glutamate and/or amyloid, neuronal killing is enhanced.90 Oxidized LDL is toxic to motor neuron cells, possibly linking it to amyotrophic lateral sclerosis. 91 Antioxidants, just as in the case of plasma lipoproteins, reduce oxidized LDL and HDL neurotoxicity.92 Homocysteine has been strongly associated with cardiovascular disease, even though the mechanism has not been fully elucidated. Less well appreciated is the connection between elevated levels of homocysteine and neurodegeneration. Several recent studies have shown a strong correlation between homocysteine levels and incidence of Alzheimer’s disease.93,94 Rarely discussed is the fact that homocysteine is an excitotoxin, as are homocysteic and homocysteine sulphinic acid,95 two of its metabolic breakdown products. These excitotoxins act at the N-methyl-D-aspartate (NMDA) receptor, triggering the entry of excessive amounts of calcium into the neuron, leading to numerous destructive reactions including the generation of peroxynitrite, 4-HNE, hydroxyl and peroxyl radicals, and activation of the eicosanoid cascade. Whether lowering homocysteine levels will reduce Alzheimer’s disease is as yet unknown. We do know that folate, pyridoxine, and antioxidant vitamin deficiencies are common in Alzheimer’s disease patients.96,97 Several studies have shown low levels of vitamin B12 as well.97 It is important to appreciate that the classical hematological signs of B12 deficiency, macrocytosis and hypersegmented neutrophils, are usually absent in these patients.98 While homocysteine levels were found to be consistently elevated in Alzheimer’s patients, nutritional deficiency was not confirmed using retinol binding protein (RBP). This indicates an impaired cobalamin delivery to the tissues, which explains the observed discrepancy between normal serum levels of cobalamin and folate and low tissue metabolic products found frequently in the elderly. One recent study throws the homocysteine theory into question.99 Centenarians living in two northern Italian provinces were examined for blood levels of homocysteine, folate and B12. They examined centenarians who were cognitively normal, cognitively impaired, and those with a diagnosis of Alzheimer’s disease. Elevated homocysteine levels were found in 77% of normal, 100% of cognitively Winter 2002 Vol. 5, No. 1 JANA 20 impaired, and 82% of Alzheimer’s patients. Demented centenarians had the lowest folate levels. Low B12 and B6 levels were found in 33% and 66% respectively of all centenarians regardless of cognitive status. There are several explanations for these negative findings. First, the study was based on blood levels of the vitamins, and as we have seen, there is little correlation between blood levels and tissue levels of these three vitamins. As for the lower level of homocysteine seen in the centenarian Alzheimer patients, perhaps it was secondary to metabolic burnout, something we see in the case of glutamate as well. Homocysteine is known to elicit apoptosis quite rapidly when hippocampal neurons are exposed to this amino acid.100 The mechanism includes DNA strand breaks with activation of poly-ADP-ribose polymerase (PARP) which depletes nicotinamide adenine dinucleotide) (NAD). This in turn leads to mitochondrial dysfunction, oxidative stress and caspase activation. In essence it markedly enhances the vulnerability of hippocampal neurons to excitotoxic and oxidative injury. ENERGY PRODUCTION, EXCITOTOXICITY. AND FREE RADICALS There is an intimate connection between energy production, excitotoxicity, and free radicals. It has been known for some time that impaired mitochondrial energy production can lead to dramatic increases in free radical production, and that reduced neuronal energy production significantly increases the neuron’s sensitivity to excitotoxicity.101 In fact, under such conditions even normal concentrations of extracellular glutamate can trigger excitotoxic reactions. Further, an increase in free radical production, either as reactive oxygen or reactive nitrogen species, increases the release of glutamate from the astrocyte. Glutamate in turn increases free radical production, which further reduces energy production. This vicious cycle continues until the p53 gene is activated and apoptosis ensues. The neurons are destroyed by necrosis as well. When elevated iron levels are present, as it does in all neurodegenerative disorders, free radical generation reactions are accelerated. Another result of increased free radical generation is its effect on the blood-brain barrier system. This gatekeeper normally prevents or slows the passage of harmful molecules into the brain’s environment. Unfortunately, the system is not perfect. Recent studies have shown that free radicals can open the barrier, allowing harmful compounds inside, including the excitotoxins glutamate and aspartate. 102 Evidence also indicates that the barrier contains glutamate receptors and that glutamate itself can open the barrier.103 This means that elevated levels of blood glutamate can open the barrier, further elevating the level of this powerful excitotoxin in the extracellular space. Related to energy deficits in neurodegeneration is the finding that the glucose transporter is impaired in Alzheimer’s disease secondary to alteration in the brain’s vasculature.104 In addition, glutamate itself can impair glucose entry into the brain. So we see that there is an intimate connection between glutamate, free radicals, energy production, and the widespread destruction of neurons. Because neurons differ in the types of neurotransmitter receptors present on their membranes, some will be more sensitive than others.. This accounts for the difference in pathological presentation. Reduced energy production has been demonstrated in all four major neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. In each instance, specific enzyme deficiencies are present. In Parkinson’s disease, complex I is deficient.105 In Alzheimer’s disease complex I, IV and pyruvate dehydrogenase complex are all deficient. 106,107 MAGNESIUM Magnesium plays a special role in excitotoxicity and free radical generation. The magnesium receptor is located near the calcium channel on neurons possessing the NMDA receptor, which regulates calcium entry into the neuron. As we have seen, excessive intracellular calcium can trigger destructive reactions involving nitric oxide synthase induction, arachidonic acid release from the membrane with eicosanoid activation, and changes in mitochondrial function. Magnesium can block calcium entry as long as the neuron is not firing. It has been demonstrated that low magnesium levels greatly enhance the neuron’s sensitivity to glutamate, again, where even normal levels can be excitotoxic.108 Other studies indicate that magnesium plays a major role in preventing free radical accumulation.109 Cells isolated in a low magnesium environment not only generate more free radicals but are twice as sensitive to free-radicalinduced cell death as cells with normal magnesium levels.110 In addition, hypomagnesmia lowers the cell’s glutathione level and increases its cytokine level, which, as we have seen, can inhibit glutamate uptake, thereby increasing free radical generation that leads to excitotoxic neuron death. Both experimental and clinical studies have demonstrated significant neuroprotective effects of elevated magnesium levels.111,112 An additional benefit is that magnesium also inhibits the entry of oxidized lipids into the endothelial cells of blood vessels.
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with much love, lou_lou . . by . , on Flickr pd documentary - part 2 and 3 . . Resolve to be tender with the young, compassionate with the aged, sympathetic with the striving, and tolerant with the weak and the wrong. Sometime in your life you will have been all of these. |
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09-02-2007, 11:30 PM | #6 | |||
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In Remembrance
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INHIBITORS OF GLUTAMATE UPTAKE: THE
GLUTAMATE TRANSPORT PROTEINS Because even small concentrations of extracellular glutamate can trigger neuron destruction, it is carefully reg21 JANA Vol. 5, No. 1 Winter 2002 ulated by a special re-uptake system. This system consist of approximately five different transport proteins, EAAT 1-5, whose job it is to bind to glutamate, transport it to the astrocyte and transfer it into the intercellular compartment. Once this is done, the glutamate is converted into glutamine and stored until needed. The distribution of the different types of transport proteins is brain specific.113 EAAT 1-5 are found in the retina. There is growing evidence that abnormalities in these transport proteins play a major role in many neurodegenerative diseases. This is best demonstrated in amyotrophic lateral sclerosis (Lou Gehrig disease).114 There is some evidence that a similar process operates in Alzheimer’s dementia and Parkinson’s disease.115,116 We now know that several events and compounds (such as viral infections,117 hereditary SOD1 mutants in ALS,118 oxidative stress119 and exposure to mercury) can trigger excitotoxicity by inhibiting the glutamate transporters. Mercury is a very potent inhibitor of glutamate transporters. In one study a mercury dose as low as 10(-5)M was found to be inhibitory.120 Mercury is unique, since no other metal tested, including aluminum, lead, cobalt, strontium, cadmium and zinc, had any effect on glutamate transport.121 What makes this important is the ubiquitous nature of mercury exposure. The number one source for humans is dental amalgam.122 Other sources include industrial fumes, coal burning, contaminated fish and contaminated lakes and streams. Dental amalgam is composed of 50% mercury, which has been shown to vaporize in the mouth, especially in the presence of heat. Drinking hot liquids and chewing has been shown to increase the release of mercury vapor from amalgams at levels 3X higher than normal for 90 minutes. 123,124 Over 80% to 90% of this vapor is absorbed into the circulation. Because of its fat solubility, mercury accumulates in high levels in the nervous system and is very difficult to remove.125 Mercury is also a potent stimulus for the production of free radicals and it inhibits numerous enzymes, including the antioxidant enzymes.126 As I demonstrated earlier, a key player in excitotoxicity and neurodegenerative diseases is 4-hydroxynonenal (4- HNE), a product of lipid peroxidation, and a potent inhibitor of glutamate transport proteins.127 This once again forges a strong connection between excitotoxicity and oxidative stress. Inflammatory cytokines, such as IL-1ß, IL- 2, IL-6 and TNF-alpha, can also inhibit the glutamate transporters, likely via increased lipid peroxidation and production of excessive amounts of 4-hydroxynonenal. So we see that anything that increases oxidative stress in the nervous system over a long period of time will increase the risk of neurodegeneration. This explains why so many seemingly unrelated factors – such as viral infections, trauma, pesticide exposure, hereditary enzyme defects, and exposure to mercury, aluminum, fluoride and iron can play a role in producing the neurodegenerative diseases. They all increase oxidative stress, inhibit glutamate transport, activate microglia, and trigger excitotoxicity. THE USE OF NUTRACEUTICALS AND PLANT EXTRACTS IN PREVENTING AND TREATING NEURODEGENERATION A principal cause of neurodegeneration, oxidative stress, can be substantially reduced by the consumption of various nutraceuticals.128 Flavonoids are powerful, versatile antioxidants whose potency is enhanced when combined with vitamins and minerals. ANTIOXIDANT EFFECTS Most are familiar with the antioxidant effects of vitamins such as the tocopherols and tocotrienols, ascorbate, vitamins D and K, and the minerals zinc, magnesium and selenium. As efficient as these antioxidants are, especially in combination, they are ineffective against some of the major free radicals and reactive nitrogen species. Astudy of Alzheimer’s and multi-infarct dementia patients found that both were more often deficient in vitamin E and beta carotene than matched controls.129 Only the Alzheimer’s patients were deficient in vitamin A. A number of antioxidants have been shown to inhibit glutamate-induced cytotoxicity (excitotoxicity) including vitamin E, Ginkgo biloba extract, pycnogenol, N-acetyl Lcysteine, alpha lipoic acid, DHLA, and individual flavonoids.130 Of even greater interest is the finding that not only can flavonoids protect DNA from oxidative injury, they initiate fast chemical repair of DNA as well.131 As we have seen, peroxynitrite plays a central role in neurodegeneration because of its toxic effects on mitochondrial enzymes and mitochondrial DNA. While the antioxidant vitamins are generally ineffective in inhibiting these radicals, flavonoids are quite efficient. In fact, a study of the scavenging capacity of flavonoids as compared to a standard peroxynitrite scavenger, ebselen, found that the flavonoids were 10X more potent.132 Researchers recently found that teas, both black and green, have peroxynitrite scavenging ability equal to that of red wine polyphenols.133 In their study, lipopolysaccharideinduced nitric oxide synthease (iNOS) activity was dramatically reduced, most likely by epigallocatechin gallate, but the mixed theoflavins from black tea were also potent inhibitors. Peroxynitrite is formed when nitric oxide is produced in excess. The black tea component, theaflavin digallate, was also found to decrease superoxide production in macrophages and to chelate iron to a significant degree, moreso than green tea components.134 Curcumin, from the spice turmeric, is also a potent inhibitor of peroxynitrite and lipid peroxidation.135 By Winter 2002 Vol. 5, No. 1 JANA 22 enhancing the production of glutathione, curcumin further protects neurons from peroxynitrite, as well as numerous other free radical oxygen and nitrogen species. Alpha lipoic acid and its reduced form, dehydrolipoic acid (DHLA) also enhances cellular glutathione production. Studies have shown alpha lipoic acid to increase glutathione levels from 30 to 70% higher than normal.136 Hydroxytyrosol, found in extra virgin olive oil, is highly protective against the peroxynitrite radical as well.137 Ubiquinone (coenzyme Q10) may act as a significant antioxidant in biological systems. It may do this by regenerating vitamin E.138 In turn, alpha-lipoic acid can increase the level of ubiquenol in the face of oxidative stress.139 So we see a complex interplay of the antioxidants that allows them to be regenerated for further use. The reduced form of alpha-lipoic acid, DHLA, has the greatest versatility in neutralizing free radicals. DHLA can neutralize the hydroxyl radical, singlet oxygen, hypochlorite, NO radicals, superoxide, peroxyl radicals and H202, whereas alpha-lipoic acid cannot neutralize superoxide or peroxyl.140 In mammalian cells alpha-lipoic acid is rapidly converted to DHLA.141 Both alpha-lipoic acid and DHLA have been shown to be protective against NMDA and malonic acid-induced striatal lesions in the brain, reducing the size of the lesion by 50%.142 This would be important in preventing the oxidative stress lesion responsible for Parkinson’s disease. Melatonin is also gaining interest as a powerful neuroprotectant. It has been shown to react with the hydroxyl radical, hydrogen peroxide, singlet oxygen, peroxynitrite, nitric oxide, and hypochlorus acid.143 In addition, it stimulates the production of the antioxidant enzymes: superoxide dismutase, glutathione peroxidase and glutathione reductase. In a test using dopamine, neuronal cell cultures grown in vitro in a medium without supporting growth factors, all of the cells were dying within a short period of time.144 When melatonin was added to the suspension, nearly all of the dying cells were rescued, including tyrosine hydroxylase positive DA neurons. PREVENTION OF LDL OXIDATION As we have seen, LDL and HDL exist in the brain and when oxidized can induce neuron cytotoxicity. It is interesting to note that oxidized LDL cytotoxicity acts through the NMDAreceptor by way of the excitotoxic mechanism. One major system preventing lipoprotein oxidation is the arrangement of tocopherol molecules within the LDL and HDL units. The LDL structure contains six tocopherol molecules. As with all tocopherols, those in lipoproteins can become oxidized when exposed to excessive oxidative stress. Regeneration of embedded tocopherol depends on other antioxidants, such as the carotenoids, ascorbate, alphalipoic acid, DHLA, coenzyme Q10, and the flavonoids. Dietary supplementation with alpha-tocopherol has been shown to reduce the oxidative modification of LDL, a reduction even greater in diabetics.145 Ascorbate has also been shown to be an effective inhibitor of LDL oxidation, and combined with alpha-tocopherol, has reduced the susceptibility of LDL to oxidation at all concentrations of copper tested.146 Coenzyme Q10 has been shown to significantly reduce the oxidizability of LDL in the face of aqueous free radical generation at a dose of 300 mg a day in humans.147 Numerous flavonoids have been shown to reduce LDL-oxidizability including red wine polyphenols (catechins), myricetin, quercetin, epigallocatechin gallate, epicatechin and rutin.148 I would caution that drinking red wine for health benefits may be more hazardous because of the high concentration of fluoride in California wines and the use of sulfites in most wines.149 The sulfite connection is especially strong because of the observed enhancement of neuronal toxicity when sulfite exists in the presence of peroxynitrite, especially when combined with glutathione depletion, as is seen in Parkinson’s disease.150 Finally, the alcohol itself is particularly toxic to neurons. A recent study found a graded deleterious effect of alcohol on antioxidant levels within synaptosomes and neuronal mitochondria.151 There was also a dose-dependent increase in lipid peroxidation. A recent study found that the most effective protection against oxidized LDL-induced cytotoxicity was from cyanidin, epicatechin and kaempferol, with 80% protection.152 One of the most effective flavonoids, epicatechin, was 10X more efficient in protecting neurons under these conditions than ascorbate. Pretreatment with taxifolin, apigenin and naringenin enhanced the toxic effect of oxidized LDH in vitro, even though they were not neurotoxic alone. This study demonstrates the usefulness of selected flavonoids as powerful neuroprotectants under conditions of oxidative stress. The double advantage to lowering LDL and HDL oxidation is a reduction in both direct neurotoxicity of oxidized LDL and HDL, and the prevention of atherosclerotic cerebrovascular disease. INFLAMMATION, CYTOKINES AND NUTRACEUTICALS All of the major neurodegenerative disorders are associated with microglial activation and excessive production of cytokines IL-1beta, IL-6, and TNF-alpha.153 This inflammatory process involves overactivation of the eicosanoid system through activation of phospholipase A2 and the release of arachidonic acid from the membrane. This in turn is acted on by lipoxygenase and cyclooxygenase with the production of numerous pro-inflammatory leukotrienes and prostaglandins. Excitotoxins also induce interleukin-1beta both in microglia and astrocytes.154 23 JANA Vol. 5, No. 1 Winter 2002 Attempts to reduce neurodegeneration have recently focused on ways to inhibit this series of pro-inflammatory reactions. In one transgenic Alzheimer’s mouse model study, it was found that ibuprofen significantly reduced IL- 1beta and glial fibrillary protein levels and reduced the total number of amyloid deposits.155 Another cytokine of importance in neurodegeneration is tumor necrosis factor-alpha (TNF-alpha), which is elevated in Alzheimer’s disease, Parkinson’s disease, and ALS. It is known that (-) epigallocatechin gallate inhibits the production of TNF-alpha by modulating the pro-inflammatory transcription factor NF kappa B. Other flavonoids, such as curcumin and quercetin,156,157 can also modulate NF kappa B. In one study, all flavonones tested protected cells against TNF cytotoxicity, with eriodictyol being most potent.158 Apigenin markedly enhanced the cytotoxicity of TNF. Zinc has been shown to markedly inhibit apoptosis induced by TNF.159 Critical to the neurodegenerative process is the inflammatory cascade, which involves numerous cytokines, eicosanoids, and other immune factors. We know there is an intimate connection between excitotoxicity and the inflammatory cascade in cells. The inflammatory cascade can be blocked or reduced at any one of these levels. Since NF-kappa B transcription factor plays a major role in CNS inflammation, blocking its activity can reduce inflammation, making quercetin, apigenin, and curcumin especially useful in this regard.160 Some flavonoids inhibit the release of arachidonic acid from the membrane.161 These include amentoflavone (Ginkgo leaf), quercetagetin-7-0-glucoside, apigenin, fisetin, kaempferol, luteolin, and quercetin. Apigenin, genistein, and kaempferol have been found to be potent inhibitors of the COX-II enzyme, which is responsible for inflammatory reactions.162 Curcumin is also a potent inhibitor of the COX enzymes and is equal in potency to NSAIDs.164 They also inhibit inducible nitric oxide synthease (iNOS), which triggers the production of the powerful and destructive peroxynitrite radical. Quercetin, which significantly inhibits COX enzymes, is a more potent inhibitor of lipoxygenase (LOX).163 Interleukin-12 also plays a vital role in inflammation; it is potently inhibited by the flavonoid curcumin. In addition, curcumin has been shown to potently inhibit prostaglandin activation in cases of toxic damage to the brain by alcohol.165 So we see that flavonoids act at multiple sites to inhibit the destructive reactions precipitated during neurodegeneration, including excitotoxicity, microglia activation, glutamate transporter inhibition, transitional metal activation of free radicals, and direct inhibition of the inflammatory processes. Finally, there is some evidence that one herb, Ashwagandha, can act as an immune modulator.166 That is, it can suppress an overactive immune response. IMPROVING ENERGY PRODUCTION As we have seen, cellular energy production plays a pivotal role in protection against excitotoxicity. At present, there are numerous ways to improve mitochondrial energy generation. Of great importance in neurodegenerative disorders is the ability to bypass blocks in the electron transport chain, as is seen in both Parkinson’s and Alzheimer’s disease. For example, coenzyme Q10, succinate, and ßhydroxybutyrate have all been shown to bypass complex I defects.167 Pyruvate and malate have been shown to protect cortical neuron cultures from excitotoxic cell death following exposure to glutamate, mostly by increasing cell energy generation.168 Supplementation with creatine also protects against excitotoxic injury.169 Many other vitamins and minerals play a role in cellular energy production, including magnesium, thiamine, riboflavin, niacinamide, menadione, tocopherols, folate, ascorbic acid, succinate, acetyl-L-carnitine, and alphalipoic acid.170 Acetyl-L-carnitine has been shown to partially restore mitochondrial function in elderly rats,171 while treatment of old rats with alpha-lipoic acid has been shown to improve mitochondrial energy production and increase their metabolic rate.172 Protecting the cell, and its mitochondria, from the effects of free radicals plays a key part in preserving cellular energy production. Remember, mitochondrial DNA is 10X more sensitive to free radical injury than is nuclear DNA. DIRECT BLOCKING OF EXCITOTOXICITY Several nutrients can directly block the excitotoxic process itself. For example, methylcobalamin has been shown to block the NMDA glutamate receptor on the neuron. 173 Pycnogenol has been shown to inhibit the cytotoxic effects of amyloid ß-protein and to protect hippocampal neurons from high concentrations of glutamate.174 The natural product vinpocetine not only increases cerebral blood flow but also inhibits glutamate receptors and regulates Na+-channels, offering potential benefits against neurodegenerative disorders.175 Low doses of vitamin D have been shown to protect neurons by down-regulating Ltype voltage-sensitive calcium channels, thereby protecting hippocampal neurons in culture from excitotoxcicity.176 Another way flavonoids may help prevent excitotoxic lesions in the nervous system is by reducing histamine release and activity. A recent study found that activated mast cells in the CNS increased excitotoxic injury 60% by potentiating receptor-mediated events at the NMDA receptor. 177 Vitamin C inhibits the release of histamine from mast cells, and quercetin blocks the histamine receptor. While neuroprotection by quercetin’s action on brain histamine has not been demonstrated, it deserves a closer look. Combining nutrients appears to offer more neuroproWinter 2002 Vol. 5, No. 1 JANA 24 tection than using single agents. In one study, combining coenzyme Q10 and nicotinamide significantly protected striatal neurons in vivo, against excitotoxic destruction, while CoQ10 alone was not protective.178 Likewise, vitamin C and alpha-tocopherol used in combination inhibited lipid peroxidation in mice brains significantly better than either agent used alone.179 OTHER NEUROPROTECTIVE NUTRACEUTICALS Docosahexaenoic acid (DHA) is essential for the normal development and function of the infant brain and for the maintenance of the adult brain. It should be remembered that the adult brain is constantly remolding itself, a process called plasticity. This remodeling process primarily involves synaptic reorganization. Considerable scientific literature confirms the importance of docosohexanoic acid (DHA) in this process.180 Because of the widespread consumption of processed foods, deficiencies of DHA are common. The ratio of N-6 fats to N-3 fats is now 25:1 when it should be 5:1.181 DHA reduces the risk of neurodegeneration not only by improving cerebral plasticity, but also by reducing inflammation.182 Without antioxidant supplementation, DHA alone can increase free radical production and lipid peroxidation. A fairly recent study found significant abnormalities in amino acid metabolism in Alzheimer’s disease patients.183 Significantly reduced plasma amino acids included tryptophan and methionine. Excessive supplementation with serotonin precursors could potentially lead to increased excitotoxic injury due to a buildup of the serotonin metabolic product quinolinic acid, a known excitotoxin. Taurine has been shown to have neuromodulatory effects in the CNS and to regulate cell volume.184 Another study found low levels of s-adenosylmethionine in Alzheimer’s patients.185 A postmortem study of 11 patients with Alzheimer’s disease found low levels of sadenosylmethionine in all areas of the brain as compared with matched controls. In this same study, normal levels were found in cases of Parkinson’s disease, demonstrating that a low level of s-adenosylmethionine was not merely an epiphenomenon of neurodegeneration. No studies have been done to supplement Alzheimer’s patients with sadenosylmethionine. It may be that these low levels merely reflect a deficiency in folate, pyrodoxine, and cobalamin, which is known to occur in Alzheimer’s disease.186 Chronic folate deficiency has been associated with cancer and may also have a significantly deleterious effect on brain function as well, especially when combined with prolonged injury by reactive oxygen and nitrogen species. Growing evidence indicates that several hormones can protect neurons from numerous types of injury including neurodegeneration. The earliest attention was given to estrogen hormones and their ability to attenuate the symptoms of Parkinson’s disease.187 More recent studies have shown that estrogens are essential for maintaining the nigrostriatal dopamine neurons and that the number of dopamine neurons in females is higher because of the estrogen stimulation.188 Alzheimer’s disease is significantly reduced in postmenopausal women taking estrogen supplementation as compared with unsupplemented controls.189 Estrogen acts at several levels to protect neurons. Estrogens are trophic factors for cholinergic neurons that modulate the expression of Apo-E, act as an antioxidant, and inhibit the formation of amyloid beta-peptide. Estrogenic phytonutrients such as genistein, exhibit neuroprotective effects against excitotoxicity.190 Several flavonoids, such as quercetin, have significant estrogenic activity. In addition to its neuroprotective estrogenic activity, quercetin is a powerful and versatile antioxidant. While estrogen may play a role in preventing Alzheimer’s disease, one recent study found no evidence that it slows the progression of mild to moderate Alzheimer’s disease in women.191 The problem with this trial is that the estrogen used was premarin, which has been shown to break down into neurotoxic products itself. Natural hormones have not been tried in clinical trials. Experimentally, the phytoestrogen from quercetin and apigenin did significantly inhibit amyloid ß-protein-induced cytotoxicity. Soy-based phytoestrogens have also been shown to protect neurons in vivo.192 Dehydroepiandrosterone sulphate (DHEA-S) also has been shown to be generally neuroprotective.193 In addition, it protects hippocampal neurons against glutamate-induced excitotoxicity.194 While DHEA-S levels tend to fall with age, the levels are significantly lower in Alzheimer’s disease. Pregnenolone sulfate, a precursor to steroid hormones acting higher up the ladder than DHEA, has been shown to protect animals against spinal cord injury.195 The serum levels of pregnenolone, in one study, fell as much as 60% by the mean age of 75 years as compared to levels at age 35.196 There is new evidence that testosterone may protect men from Alzheimer’s disease, apparently by decreasing the secretion of amyloid ß-peptide from neurons. Several plant extracts have shown an ability to increase testosterone secretion in both males and females. Several water-soluble vitamins have shown promise in preventing excitotoxic-neurodegenerative injury to the nervous system. For example, nicotinamide has been shown to reduce the size of a middle cerebral infarction in a dosedependent manner for up to two hours after vessel occlusion in a stroke model.198 It has also been demonstrated to enhance brain choline levels 199 and reduce apoptosis-associated DNA fragmentation, commonly seen in the Alzheimer brain.200 Despite the fact that at least one study found low levels of vitamin C in Alzheimer’s patients, no trials have been done supplementing these patients with 25 JANA Vol. 5, No. 1 Winter 2002 ascorbate.201 In this study, plasma vitamin C levels fell in proportion to the severity of the disease. Two herbs, Ginkgo biloba and Panax ginseng, have shown both clinical and experimental promise in preventing and treating neurodegenerative disorders,. In a doubleblind, randomized, placebo-controlled clinical study involving 309 patients with mild to moderate Alzheimer’s dementia, researchers found that moderately low doses of Ginkgo extract (EGb 761) could slow the course of the disease and improve mental functioning in a substantial number of patients.202 Another study using 240 mg of Ginkgo biloba extract also found substantial benefit in Alzheimer’s patients with a wide margin of safety.203 In another trial, 256 healthy, middle-aged volunteers were given either 160 mg or 320 mg of a mixture of standardized Ginkgo biloba and Panax ginseng for 14 weeks.204 At the end of the trial, substantial improvements in both working and long-term memory were seen, an effect that lasted beyond the two-week washout at the end of the trial. Studies have shown that Ginkgo biloba extract can protect neuron membranes against hypoxia-related breakdown, something that probably plays a vital role in Alzheimer’s disease.205 By its powerful antioxidant effects, Ginkgo biloba demonstrates an ability to preserve mitochondrial function in aged animals, which, as we have seen, is vital to preventing accumulative excitotoxic-free radical injury.206 Ginsenosides Rb1 and Rg3 have been found to significantly protect cultured rat cortical neurons from neurodegeneration precipitated by excess glutamate.207 Important in preventing Alzheimer’s-type neurodegeneration, Rb1 increases choline acetytransferase in the basal forebrain and nerve growth factor in the hippocampus.208 This also explains the finding of improved memory function in scopolamine-treated young and old rats treated with ginsenosides Rb1 and Re.209 Finally, one naturally found substance with much promise is GM-1 ganglioside. In experiments using monkeys treated with 1-methyl-1,4-phenyl-1,2,3,6-tetrahydropryidine (MPTP) to induce Parkinson’s disease, GM-1 ganglioside was found to exert a neurotrophic effect on the surviving neurons in the substantia nigra.210 In another study, GM-1 ganglioside was found to protect against motor neuron death in rats,211 and to reduce by half the number of degenerating fibers in their spinal cords following injury. REDUCING MERCURY TOXICITY Mercury is one of the most neurotoxic elements found in nature. Unfortunately, millions of people are being put at unnecessary risk by having dental amalgam placed in their teeth as a restorative. Amalgam contains approximately 50% mercury. Another common source is thimerosal, a preservative in some vaccines. With tens of millions of babies and children being vaccinated each year with up to 33 vaccinations before age two, a frightening health disaster is in the making. There is no known safe level of mercury. The ability of our cells to resist toxins depends on their overall health and especially their antioxidant capacity. It has been demonstrated that one’s sensitivity to mercury is directly related to tissue levels of alpha-tocopherol and selenium,212 especially in the nervous system. Zinc may protect the nervous system from mercury toxicity via its role in the production of metallothionein. While no one has tested the ability of plant flavonoids to chelate mercury, several, including curcumin, hesperidin, quercetin, tea catechins, and rutin, have been shown to have powerful chelating ability for iron and copper. Mercury has been shown to powerfully bind with citrate and malate to form a harmless compound.213 In addition, both easily penetrate the blood-brain barrier. Removal of mercury from the brain is a difficult and slow process, but by utilizing these organic compounds one can significantly reduce its toxicity. Combining magnesium to malate and citrate would further reduce mercury toxicity by their combined ability to reduce NMDA activity, increase cellular glutathione levels and reduce free radical injury. Garlic extract has also been shown to efficiently remove mercury from the brain.214 In fact, it is almost as efficient as 2,3-dimercaptosuccinic acid (DMSA). In addition, garlic binds and removes mercury within the GI tract, the major reservoir for mercury. The active principle may be selenium.215 High doses of alpha-lipoic acid, a powerful and versatile antioxidant, are also an efficient chelator of mercury.216 It easily penetrates the blood-brain barrier and has been shown to reverse the age-related changes in long-termed potentiation (LTP) responsible for laying down memory.217 Since mercury in brain tissue is associated with dramatic increases in free radical formation, all preceding comments concerning antioxidant supplements and flavonoids apply.218 In addition, recent studies have directly linked neuron exposure to mercury with the formation of ß-amyloid as well as hyperphosphorylation of the tau protein. This is most likely related to both free radical generation and direct effects of mercury on amyloid ß protein and tau phosphorylation. Finally, exposure to mercury induces autoantibodies to neurotypic and gliotypic proteins, common to all three of the major neurodegenerative diseases.220 Mercury exposure has been shown to increase the number of microglia cells in the brain, wherein the mercury accumulates.221 Again, all nutritional factors affecting the immune response would apply here. Winter 2002 Vol. 5, No. 1 JANA 26 SUMMARY We have seen that neurodegeneration is a complex process involving several cellular systems including free radical generation, the antioxidant network, eicosanoid activation, lipid peroxidation products that inhibit glutamate re-uptake, a loss of cellular energy production, and the buildup of advanced glycation end products. All of these processes are connected to the excitotoxic reaction. That chronic inflammation may be the central cause of neurodegenerative diseases is only one part of the puzzle. Overactivation of the glutamate receptors will trigger activation of the microglia, leading to the immune–cytokine activation process, and will trigger a tremendous generation of reactive oxygen and nitrogen species. This in turn leads to impairment of the energy-generating system, primarily by the action of free radicals (peroxynitrite and hydroxyl ions) on the mitochondrial DNA and electron transport system enzymes. While different triggering events can initiate these destructive processes at any level, all result in glutamate receptor overactivity and initiaton of the excitotoxic process. We have seen that several nutraceuticals can act at one of multiple levels in this destructive process. The flavonoids, in fact, operate simultaneously at many arms of the excitotoxic reaction. One key to preventing neurodegeneration is to maintain the cell’s energy supply. Events that interfere with cellular energy production, no matter the cause, will result in neurodegeneration. Nutraceutical research remains an area of much promise in conquering this dreaded process. REFERENCES 1. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway in neurologic disorders. N Eng J Med. 1994;330:613-622. 2. Blaylock RL. Neurodegeneration and aging of the central nervous system: prevention and treatment by phytochemicals and metabolic nutrients. Integrative Med. 1998;1:117-133. 3. Seal RP, Amara SG. Excitatory amino acid transporters: a family in flux. Ann Rev Pharmacol Toxico. 1999;39:431-456. 4. Seeburg PH. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 1993;16:359-364. 5. Churn SB, Sombati S, et al. Excitotoxicity affects membrane potential and calmodulin kinase II activity in cultured rat cortical neurons. Stroke. 1993;24:271-278. 6. Lipton SA. Prospects for clinically tolerated NMDA antagonist: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci. 1993;16:527-532. 7. Torreilles F, Salman-Tabcheh S, et al. Neurodegenerative disorders: the role of peroxynitrite. Brain Res Rev. 1999;30:153-163. 8.Worley PF, Baraban JM, Snyder SH. Beyond receptors: multiple second-messenger systems in brain. Ann Neurol. 1987;21:217-229. 9. Prasad KN, Hovland AR, et al. Prostaglandins as punative neurotoxins in Alzheimer’s disease. Proc Soc Exp Biol Med. 1998;219:120-125. 10. Kristal BS, Chen J, Yu BP. Sensitivity of mitochondrial transcription to different free radical species. Free Radic Biol Med. 1994;16:323-329. 11. Keller JN, Mark RJ, et al. 4-hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience. 1997;80:685-696. 12. Blakeman DP, Ryan RA, et al. Protein oxidation: examination of potential lipid-independent mechanisms for protein carbonyl formation. J Biochem Molecular Toxicol. 1998;12:185- 190. 13. Stadtman ER. Protein oxidation and aging. Science. 1992;257:1220-1224. 14. Ames BN, et al. Oxidants, antioxidants, and degenerative diseases of aging. Proc Nat Acad Sci USA. 1993;90: 7915-7922. 15. Burcham PC. Genotoxic lipid peroxidation products: their DNA damaging properties and role in formation of endogenous DNA adducts. Mutagenesis. 1998;13:287-305. 16. Lane DP, Midgley CA, et al. On the regulation of the p53 tumor suppressor, and its role in the cellular response to DNA damage. Philos Trans R. Soc Biol Sci. 1995;347: 83-87. 17. Hamos JE, DeGennaro LJ, Drachman DA. Synaptic loss in Alzheimer’s disease and other dementias. Neurology. 1989;39:355-361. 18. Behl C, Davis JB, et al. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994;77:817-827. 19. Mattson MP, Cheng B, Davis D, et al. ß-amyloid peptides destabilizes calcium homeostasis and renders human cortical neurons vulnerable to excitotoxicity. J Neurosci. 1992;12:376-389. 20. Mattson MP, Fu W, Eaeg G, Uchida K. 4-hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau. Neuroreport. 1997;8:2275-2281. 21. Mattson MP. Antigenic changes to those seen in neurofibrillary tangles are elicited by glutamate and Ca+2 influx in cultured hippocampal neurons. Neuron. 1990;2: 105-117. 22. Stoll G, Jander S. The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol. 1999;58: 233-247. 23. Banati RB, Gehrmann J, et al. Cytotoxicity of microglia. Glia. 1993;7:111-118. 24. Markesbery WR, Ehmann WD, et al. Brain trace element concentration in aging. Neurobiol Aging. 1984;5:19-28. 25. Johnson S. Iron catalyzed oxidative damage, in spite of normal ferritin, and transferritin saturation levels and its possible role in Werner’s syndrome, Parkinson’s disease, cancer, gout, rheumatoid arthritis, etc. Med Hypotheses. 2000;5:242-244. 26. Leveugle B, Faucheux BA, et al. Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson’s disease cases. Acta Neuropathol (Berl). 1996;91:566-572. this is a very long list -if anyone wants it in its entirety go to -dr. blaylocks site
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with much love, lou_lou . . by . , on Flickr pd documentary - part 2 and 3 . . Resolve to be tender with the young, compassionate with the aged, sympathetic with the striving, and tolerant with the weak and the wrong. Sometime in your life you will have been all of these. |
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09-03-2007, 11:48 AM | #7 | ||
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In Remembrance
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From personal experience and first hand witnessing of approaches that work:
- Reduce your sugar intake (including sweet fruits. honey). -Take multivitamin supplementation -Take extra vit.C, B-complex, magnesium, essential oils, l-carnitine, melatonine. -Any approach which improves brain blood flow is bound to do us good: ginko, gingseng, exercise(active -walk - and passive -rocking chair) -Stay away from iron, aluminum, mercury. -Stay clear from excitatory food additives: MSG, trans-fats, aspartame |
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