Glutamic acid (also called "glutamate") is the chief excitatory neurotransmitter in the human and mammalian brain (1-3). Glutamate (GLU) neurons make up an extensive network throughout the cortex, hippocampus, striatum, thalamus, hypothalamus, cerebellum, and visual/auditory system (4). As a consequence, GLU neurotransmission is essential for cognition, memory, movement and sensation (especially taste, sight, hearing) (3). GLU and its biochemical "cousin," aspartic acid or aspartate (ASP), are the two most plentiful amino acids in the brain (5). ASP is also a major excitatory neurotransmitter, and ASP can activate neurons in place of GLU (1,2).
GLU and ASP can be synthesized by cells from each other, and GLU can be made from various other amino acids, as well (5). GLU and ASP are both common in foods also. Wheat gluten is 43% GLU, the milk protein casein is 23% GLU, and gelatin protein is 12% GLU (5). One of the commonest food additives in the developed world is MSG (monosodium glutamate), a flavor enhancer. By 1972 576 million pounds of MSG were added to foods yearly, and MSG use has doubled every decade since 1948 (2). ASP is one half of the now ubiquitous sweetener aspartame (NutraSweet ®), which is the basis of diet desserts, low-calorie drinks, chewing gum, etc. (2,6). Thus, even a superficial look at GLU/ASP in brain chemistry, foods, and food additive technology indicates a major role for them in our lives. Without normal GLU/ASP neurotransmission, we would be deaf and blind mental and behavioural vegetables. Yet ironically GLU and ASP are the two major excitotoxins out of 70 so far discovered (1-3,6). Excitotoxins are biochemical substances (usually amino acids, amino acid analogs, or amino acid derivatives) that can react with specialized neuronal receptors - GLU receptors - in the brain or spinal cord in such a way as to cause injury or death to a wide variety of neurons (1-3, 8-10).
A broad range of chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, stroke (multi-infarct) dementia, amyotrophic lateral sclerosis and AIDS dementia are now believed to be caused, at least in part, by the excitotoxic action of GLU/ASP (1-3, 7-10). Even the typical memory loss, confusion, and mild intellectual deterioration that frequently occurs in late middle age/old age may be caused by GLU/ASP excitotoxity (2,6). Acute diseases and medical conditions such as stroke brain damage, ischemic (reduced blood flow) brain damage, alcohol withdrawal syndrome, headaches, prolonged epileptic seizures, hypoglycaemic brain damage, head trauma brain damage, and hypoxic (low oxygen) /anoxic (no oxygen) brain damage (e.g. from carbon monoxide or cyanide poisoning, near-drowning, etc.) are also believed to be caused, at least in part, by GLU/ASP excitotoxicity (1-3, 7-11). Medical research is focusing more and more on ways to combat excitotoxicity. A drug called "memantine" which blocks the main GLU-excitotoxicity site in neurons - the NMDA GLU receptor (more on this later) - has been used clinically in Germany with significant success in treating Alzheimer's disease since 1991. (12). Memantine's NMDA GLU-receptor blocking action has also shown promise in Parkinson's disease, diabetic neuropathic pain, glaucoma, HIV dementia, alcohol dementia, and vascular (stroke or arteriosclerosis - caused dementia (12).
Experimental NMDA - GLU receptor blockers such as MK-801 (dizocilpine) have also demonstrated the ability to reduce or eliminate brain damage from acute conditions such as stroke, ischaemia/hypoxia/anoxia, severe hypoglycaemia, spinal cord injury and head trauma (1-3). Yet the few available clinical or experimental excitotoxicity-blocking drugs so far discovered have significant side effect potential - they may block normal, essential GLU neurotransmission as well as excitotoxicity (1-3,12). Fortunately, a review of the basics of GLU excitotoxicity reveals a host of preventative nutritional/life extension drug strategies that will minimize or even eliminate the excitotoxic "dark side" of GLU/ASP.
GLU and ASP are neurotransmitters. Neurotransmitters are the chemicals that allow neurons to communicate with and influence each other. Neurotransmitters (NT) serve either to excite neurons into action, or to inhibit them. NTs are stored inside neurons in packages called "vesicles." When an electric current "fires" across the surface of a neuron, it causes some of the vesicles to migrate to the synapses and release their NT contents into the synaptic gap [see Figure 1]. The NTs then diffuse across the gap and "plug in" to receptors on the receiving neuron. When enough receptors are simultaneously activated by NTs, the neuron will either "fire" an electric current all over its surface membrane, if the transmitter/receptors are excitatory, or else the neuron will be inhibited from electrically discharging, if the NT/receptors are inhibitory. All the neural circuitry of our brains work through this interacting "relay race" of NTs inducing electrical activation or inhibition.
GLU receptors are excitatory - they literally excite the neurons containing them into electrical and cellular activity. There are 4 main classes of GLU receptors: the NMDA (N-methyl-D-aspartate) receptor, the quisqualate/AMPA receptor, the kainite receptor, and the AMPA metabotropic receptor. Each of these receptors has a different structure, and has somewhat different effects on the neurons they excite. The NMDA is the most common GLU receptor in the brain (13). The NMDA, kainite and quisqualate receptors all serve to open ion channels. Looking at the NMDA receptor diagram [See Figure 2], the NMDA receptor is the most complex, and had more diverse and potentially devastating effects on receiving neurons than the others. When GLU or ASP attaches to the NMDA receptor, it triggers a flow of sodium (Na) and calcium (Ca) ions into the neuron, and an outflow of potassium (K). It is this ion exchange that triggers the neuron to "fire" an electric current across its membrane surface, in turn triggering a NT release to whatever other neurons the just-fired neuron synaptically contacts. The kainite and AMPA ion channels primarily permit the exchange of Na and K ions, and generally cause briefer and weaker electric currents than NMDA receptors. Thus, when GLU/ASP acts through kainite/AMPA receptors, it is weakly excitatory, but when GLU/ASP act through NMDA receptors, they are strongly excitatory (14). NMDA receptor activation is the basis of long-term potentiation (LTP), which in turn is the basis for memory consolidation and long-term memory formation (14).
Looking at the NMDA receptor diagram it shows that there are receptor sites for chemicals other than GLU. The zinc site can be occupied by the zinc ion, and this will block the opening of the ion channel. The PCP site can be occupied by the drug PCP ("angel dust"), an animal tranquilliser; ketamine, an anaesthetic; MK-801, an experimental NMDA antagonist; or the previously mentioned memantine. When the PCP is occupied, the opening of the ion channel is blocked, even when GLU occupies its receptor site (1-3). The mineral magnesium (Mg) can occupy a site near to, or perhaps identical with, the PCP site. Magnesium blocks the NMDA channel in a "voltage dependent manner." This means that as long as the neuron is able to maintain its normal resting electrical potential of -90 millivolts, the Mg blocks the ion channel even with GLU in its receptor.
However, if for any reason (e.g. not enough ATP energy to maintain the resting potential) the surface membrane electrical charge of the cell drops to -65 millivolts, allowing the neuron to fire, the Mg block is overcome, and the channel opens, allowing the Na and Ca to flood the neuron (1-3). After the neuron has fired, membrane pumps then pump the excess Na and Ca back outside the neuron (15). This is necessary to return the neuron to its resting, non-firing state. Neurons in a resting state prefer to keep Ca inside the cell at a level only 1/10,000 of that outside, with Na levels 1/10 as high as outside the neuron (15). These pumps require ATP energy to function, and if neuronal energy production is low for any reason (hypoglycaemia, low oxygen, damaged mitochondrial enzymes, serious B vitamin or CoQ10 deficiency, etc.), the pumps may gradually fail, allowing excessive Ca/Na build up inside the cell. This can be disastrous (1-3).
Normal levels of Ca inside the neuron allow normal functioning, but when excessive Ca builds up inside neurons, this activates a series of enzymes, including phopholipases, proteases, nitric oxide synthases and endonucleases (1,3). Excessive intraneuronal Ca can also make it impossible for the neuron to return to its resting state, and instead cause the neuron to "fire" uncontrollably (1,3). Phospholipase A2 breaks down a portion of the cell membrane and releases arachidonic acid (AA), a fatty acid. Other enzymes then convert AA into inflammatory prostaglandin's (PG), thromboxanes (TX) and leukotrienes (LT), which then damage the cell (1,3). Phospholipase A2 also promotes the generation of platelet activating factor, which also increases cell Ca influx by stimulating release of more GLU (3). And whenever AA is converted to PGs, TXs, and LTs, free radicals, including superoxide, peroxide and hydroxyl, are automatically generated as part of the reaction (1-3, 16). Excessive Ca also activates various proteases (protein-digesting enzymes) which can digest various cell proteins, including tubulin, microtubule-proteins, spectrin, and others (1,3). Ca can also activate nuclear enzymes (endonucleases) that result in chromatin condensation, DNA fragmentation and nuclear breakdown, i.e. apoptosis, or "cell suicide" (3). Excessive Ca also activates nitric oxide synthase, which produces nitric oxide (NO). When this NO reacts with the superoxide radical produced during inflammatory PG/LT formation, the supertoxic peroxynitrite radical is formed (3,17). Peroxymtrite oxidizes membrane fats, inhibits mitochondrial ATP-producing enzymes, and triggers apoptosis (17). And these are just some of the ways GLU-NMDA stimulated intracellular Ca excess can damage or kill neurons!
Excitatory neurons using GLU as their NT normally contain a high level of GLU (10 millimoles per liter) bound in storage vesicles (3). The ambient or background level of GLU outside the cell is normally only about 0.6 micromoles per liter, i.e. about 1/17,000 as much as inside the neuron (3). Excitotoxic damage may occur to cortex or hippocampus neurons at levels around 2-5 micromoles/liter (3). Therefore the brain works hard to keep extracellular (synaptic) levels of GLU low. GLU pumps are used to rapidly return GLU secreted into synapses back into the secreting neuron, to be restored in vesicles, or to pump the GLU into astrocytes (glial cells), non-neural cells that surround, position, protect and nutrify neurons (2,3). These GLU pumps also require ATP to function, so that any significant lack of neuronal ATP, for any reason, can cause the GLU pumps to fail. This then allows extracellular GLU levels to rise dangerously (2,3). If a GLU neuron dies and dumps its GLU stores into the extracellular fluid, this can also present a serious GLU-excess hazard to nearby neurons, especially if GLU pumps are unable to quickly remove the spilled GLU (3). When GLU is pumped into astrocytes, which is a major mechanism for terminating its excitatory action, the GLU is converted into glutamine (GAM). GAM is then released by the astrocytes, picked up by GLU-neurons, stored in vesicles, and converted back to GLU as needed (3). This GLU-GAM conversion also requires ATP energy, however, and this anti-excitotoxic mechanism is also at risk if cellular energy production is comprises for any reason (3). Also, excessive free radicals can prevent GLU uptake by astrocytes, thereby significantly (and dangerously) raising extra cellular GLU levels (18).
From this brief discussion of the mechanisms of NMDA-GLU excitotoxicity, it should be clear that there are 5 main conditions which allow GLU to shift from NT to excitotoxin:
1) inadequate neuronal ATP levels (whatever the cause);
2) inadequate neuronal levels of Mg, the natural, non-drug Ca channel blocker;
3) high inflammatory PG/LT levels (caused by excessive GLU-NMDA stimulated Ca invasion);
4) excessive free radical formation (caused by PG/LT formation and/or insufficient intracellular antioxidants/free radical scavengers;
5) inadequate removal of GLU from the extracellular (synaptic) space back into neurons or into astrocytes. Addressing each of these conditions will provide appropriate nutritional/life extension drug strategies to minimize excitotoxicity.
MSG and aspartame (ASPTM) are 2 of the most widely used food additives in the modern world. MSG is a flavour enhancer (2), and ASPTM is an artificial sweetener which is the methyl ester (compound) of the amino acids phenylalamine and ASP (6). MSG is now used in a wide variety of processed foods: soups, chips, fast foods, frozen foods, canned foods, ready-made dinners, salad dressings, croutons, sauces, gravies, meat dishes, and many restaurant foods (2,7). And MSG is added not only in the form of pure MSG, but is also added in more disguised forms, such as "hydrolysed vegetable protein," "natural flavour," "spices," "yeast extract," "caseinate digest," etc. These additives may contain 20-60% MSG (2,7). Hydrolyzed vegetable protein is made by boiling down scrap vegetables in a vat of acid, then neutralizing the mixture with caustic soda. The resulting brown powder contains 3 excitotoxins: GLU, ASP and cysteic acid (2).
ASPTM is now the most widely used artificial sweetener, and is the basis for a whole industry of diet desserts, low-calorie soft drinks, sugar-free chewing gum, flavoured waters, etc. (2,6). Upon absorption into the body, ASPTM breaks down into phenylalamine, ASP, and methanol (wood alcohol), a potent neurotoxin (2,6). Between 1985 and 1988 the U.S. Food and Drug Administration received about 6,000 consumer complaints concerning adverse reactions to food ingredients. 80% of these complaints concerned ASPTM!
Excitotoxin research: The early years
In 1957, a decade after the widespread introduction of MSG into the American food supply, two ophthalmology residents, Lucas and Newhouse, discovered that feeding MSG to newborn mice caused widespread damage to the inner nerve layer of the retina. Similar, though less severe destruction was also seen upon feeding MSG to adult mice (7). In 1969, Dr. John Olney, a neuroscientist and neuropathologist, repeated Lucas and Newhouse's experiments. His research team discovered that MSG also caused lesions of the various nuclei of the hypothalamus, a key brain region that controls secretion of hormones by the pituitary gland. They also found that the MSG-fed newborn mice became obese, were short in stature, and suffered multiple hormone deficiencies (7). By 1990 it was known that GLU is the principal neurotransmitter of hypothalamic neurons (19), making this key neuroendocrine region especially sensitive to GLU excitotoxicity. Olney has continued to be a pioneer in excitotoxin research, and he coined the term "excitotoxin" in the late 1970s to describe the neural damage that GLU, ASP, and other similar chemicals can cause (8).
Defenders of the widespread use of MSG and ASPTM in the world's food supply rest their belief in the safety of MSG and ASPTM on one main premise: the protective power of the blood-brain barrier (BBB) (2,7). It is claimed that even if dietary MSG/ASPTM significantly raise blood levels of GLU and ASP, the brain will not receive any extra GLU/ASP due to the protective BBB (2,7). However, there are many reasons why this claim is false. The animal experiments cited to back this assertion are usually acute studies - that is, a single test dose of MSG or ASPTM is given, and no significant elevation of brain GLU or ASP is found (2). Yet humans eating MSG/ASPTM-laced foods and drinks don't just get a single daily dose. Those who consume large quantities of packaged, processed, or restaurant foods frequently imbibe MSG/ASPTM from breakfast to bedtime snack, even drinking ASPTM-sweetened flavoured waters in-between meals. Toth and Lajtha found that when they gave mice and rats ASP or GLU, either as single amino acids or as liquid diets, over a long period of time (days), brain levels of these supposedly BBB-excluded excitotoxins rose significantly - ASP by 61%, GLU by 35% (20).
To further worsen matters, humans concentrate MSG in their blood 5 times higher than mice from a comparable dose, and maintain the higher blood level longer than mice (2). In fact, humans concentrate MSG in their blood to a greater degree than any other known animal, including monkeys (2). And children are 4 times more sensitive to a given MSG dose than adults (2). Although food manufacturers in the U.S. removed pure MSG from their infant and children's foods in 1969 based on Olney's pioneering research (and Congressional pressure), they continued to add hydrolysed vegetable protein to baby foods until 1976, and continue to this day to add MSG-rich caseinate digest, beef or chicken broth containing MSG, and "natural flavoring" (a disguised MSG source) to baby's/children's foods (2). Since excess GLU can affect infants' and children's brain development, possibly causing "miswiring" that may lead to attention deficit disorder, autism, cerebral palsy or schizophrenia, babies and young children are especially vulnerable to GLU/ASP toxicity (2,9).
It has also been discovered that there are GLU receptors on the BBB (7). GLU appears to be an important regulator of brain capillary transport and stability, and over-stimulation of BBB NMDA receptors through dietary MSG/ASPTM- induced high blood levels of GLU/ASP may lead to a lessening of BBB exclusion of GLU and ASP (7). There are also a number of conditions that may impair the integrity of the BBB, allowing MSG/ASP to seep through. These include severe hypertension, diabetes, stroke, head trauma, multiple sclerosis, brain infection, brain tumor, AIDS, Alzheimer's disease and ageing (2,7). Certain areas of the brain, called the "circumventricular organs," are not shielded by the BBB in any case. These include the hypothalamus, the subfornical organ, the organium vasculosum, the pineal gland, the area postrema, the subcommisural organ, and the posterior pituitary gland (2). The research of Dr. M. Inouye, using radioactively labelled MSG, indicates that MSG may gradually seep into other brain areas following initial brain entry through the circumventricular organs (2).
Yet another issue that makes the BBB defence of MSG/ASPTM irrelevant is brain glucose transport. Glucose is the primary fuel the brain uses to generate its ATP energy. Continual adequate brain ATP levels are needed, as noted earlier, to prevent GLU/ASP from shifting from NTs to excitotoxins. Creasey and Malawista found that feeding high doses of GLU to mice could decrease the amount of GLU entering the brain by 35%, with even higher GLU doses leading to a 64% reduction in brain glucose content (21). Since the brain is unable to store glucose, this GLU effect alone could be a major basis for promoting excitotoxicity.
MSG/ASPTM defenders also like to point out that GLU and ASP are natural constituents of food protein, which is generally considered safe, so why the concern over MSG/ASPTM (2)? Yet there is a key difference between food-derived GLU/ASP and MSG/ASPTM. Food GLU/ASP comes in the form of proteins, which contain 20 other amino acids, and take time to digest, slowing the release of protein bound GLU/ASP like a "timed-release capsule." This in turn moderates the rise in blood levels of GLU/ASP. Also, when GLU and ASP are received by the liver (first stop after intestinal absorption) along with 20 other aminos, they are used to make various proteins. This also moderates the rise in blood GLU/ASP levels. Yet when the single amino MSG is rapidly absorbed (especially in solution - e.g. soups, sauces and gravies), not requiring digestion, human and animal experiments show rapid rises in GLU, 5 to 20 times normal blood levels (2). ASPTM is a dipeptide - a union of 2 aminos- and there exist special di- and tripeptide intestinal absorption pathways that allow rapid and efficient absorption (21). The dipeptides are then separated into free aminos, and as with free MSG there will be a rapid rise in blood ASP. Thus the characteristics of food-bound GLU/ASP and MSG/ASPTM are completely different. The phenomenon of excitotoxicity can occur even if you never use MSG/ASPTM, since neurons can produce their own GLU/ASP. Nonetheless, given the danger of even slight rises in synaptic GLU/ASP levels, prudence dictates that dietary MSG/ASPTM be avoided whenever possible, especially if you fall into the category of those with weakened BBB previously mentioned - diabetes, stroke victims, Alzheimer's patients, etc. And once you begin reading food labels, watching out not only for MSG/ASPTM, but also for "hydrolysed vegetable protein," "natural flavor," "spice," "caseinate digest," "yeast extract," etc., you will be amazed at how common MSG and ASPTM are in the modern food supply.
It should be emphasized that excitotoxicity can occur in both acute and chronic (slowly developing) forms. NMDA channel blockers such as nimodipine and memantine have shown success in blocking the dramatic change that occurs rapidly after acute excitotoxicity reactions, as in stroke, asphyxia (lack of oxygen), or head/spinal trauma (2,3,12). The chronic forms of excitotoxic brain injury will usually occur much more slowly, and the effects may be subtle until the final stage of the damage. For example, Parkinson's disease symptoms may not show up until 80% or more of the nigrostriatal neurons are destroyed, a partially excitotoxic process that may proceed "silently" for decades before symptoms present themselves (2).
Similarly, excitotoxin pioneer Olney has recently shown that there is a long, slow development of excitotoxic brain damage in Alzheimer's disease that occurs before the dramatic Alzheimer's symptoms of memory loss, disorientation, cognitive impairment, and emotional lability arise (10). So you must not assume that just because you don't notice any obvious symptoms when you consume MSG/ASPTM-containing foods, there is no excitotoxic damage occurring.
As mentioned previously, there are 5 main background factors that promote the transition of GLU/ASP from NTs to excitotoxins. These will now be examined, since they provide the rationale for a program of nutritional supplements/ life extension drugs to combat excitotoxicity.
1) Inadequate neuronal ATP levels. This factor is one of the 2 chief keys to preventing excitotoxicity. ATP is the energy "currency" of all cells, including neurons. Each neuron must produce all the ATP it needs - there is no welfare state to take care of needy but helpless neurons. ATP is needed to pump GLU out of the synaptic gap into either the GLU -secreting neuron or into astrocytes. ATP is needed by atrocytes to convert GLU into glutamine. ATP is needed by sodium and calcium pumps to get excess sodium and calcium back out of the neuron after neuron firing. ATP is needed to maintain neuron resting electric potential, which in turn maintains the Mg-block of the GLU-NMDA receptor. With enough ATP bioenergy, neurons can keep GLU and ASP in their proper role as NTs. Neurons produce ATP by "burning" glucose (blood sugar) through 3 interlocking cellular cycles: the glycolytic and Krebs' cycles, and the electron transport chain (ETC), with most of the ATP coming from the ETC (22). Various enzyme assemblies produce ATP from glucose through these 3 cycles, with the Krebs' cycle and ETC occurring inside mitochondria, the power plants of the cell. The various enzyme assemblies require vitamins B1, B2, B3 (NADH), B5 (pantothenate), biotin, and alpha-lipoic acid as coenzyme "spark plugs" (22). Mg is also required by most of the glycolytic and Krebs' cycle enzymes as a mineral co-factor (22). The ETC especially relies on NADH and coenzyme Q10 (Co Q10) to generate the bulk of the cell's ATP (22). Supplementary sublingual ATP, by supplying preformed adenosine to cells, can also help in ATP (>adenosine triphosphate) formation (22). Idebenone is a synthetic variant of CoQ10 that may work better than CoQ10, especially in low oxygen conditions, to keep ATP production going in the ETC (22). ALCAR (acetyl-l-carnitine) is a natural mitochondrial molecule that may regenerate aging mitochondria that are suffering from a lifetime of accumulated free radical damage (22). Thus the basic pro-energy anti-excitotoxic program consists of 50-100 mg of B1, B2, B3, B5; 500-10,000 mcg of biotin; 100-300 mg alpha-lipoic acid; 50-300 mg CoQ10; 45-90 mg Idebenone; 10-30 mg sublingual ATP; 500-2000 mg ALCAR; and 300-600 mg Mg; and 5-20 mg NADH. All should be taken in divided doses with meals, except the NADH, which is taken on an empty stomach.
2) Inadequate neuronal levels of Mg. Mg is nature's non-drug NMDA channel blocker. Mg is also essential, as just mentioned, for ATP production, and the small amount of ATP that can be stored in cells is stored as MgATP. Mg injections are routinely given to alcoholics going through extreme withdrawal symptoms (delerium tremens), and alcohol withdrawal is an excitotoxic process (11). Mg dietary levels in Western countries are typically only 175-275mg/day (23). Dr Mildred Seelig, a noted Mg expert, has calculated that a minimum of 8 mg of Mg/Kg of body weight are needed to prevent cellular Mg deficiency (24). This would be 560 mg/day for a 70 kg (154 pound) person. Alcoholics, chronic diuretic users, diabetics, candidiasis patients, and those under extreme, prolonged stress may need even more (25). 300-600 mg Mg per day, taken with food in divided doses, should be adequate for healthy persons. Excess Mg will cause diarrhoea; reduce dose accordingly if necessary. Mg malate, succinate, glycinate, ascorbate, chloride and taurinate are the best supplemental forms.
3) High neuronal levels of inflammatory prostaglandins (PG), thromboxanes (TX) and leukotrienes (LT). The excitotoxic process does much of its damage through initiating excessive production of PGs, TXs, and LTs. Inflammatory PGs and TXs are produced by the action of cyclooxygenase 2 (COX-2) on arachidonic acid liberated from cell membranes (16,26). LTs are produced by lipoxygenases (LOX) (16). Trans-resveratrol is a powerful natural inhibitor of both COX-2 and LOX (26,27,28).
The bioflavanoid quercetin is a powerful LOX-inhibitor (27). Curcumin (turmeric extract), rosemary extract, green tea extract, ginger and oregano are also effective natural COX-2 inhibitors (26). It is interesting to note that Alzheimer's disease is in large part an excitotoxicity disease (2,10), and 20 epidemiological studies published by 1998 indicate that populations taking anti-inflammatory drugs (e.g. arthritis sufferers) have a significantly reduced prevalence of Alzheimer's disease or a slower mental decline (26). However, both steroidal and non-steroidal anti-inflammatory drugs have potentially dangerous side effects, so the natural anti-inflammatory substances may be a much safer, if slightly less powerful, alternative. 5-20 mg trans-resveratrol 2-3 times daily, 250-500 mg quercetin 3 times daily, and 300-600 mg rosemary extract 2-3 times daily is a safe, natural anti-inflammatory program.
4) Excessive free radical formation/inadequate antioxidant status is a major pathway of excitotoxic damage. Various free radicals, including superoxide, peroxide, hydroxyl and peroxynitrite, are generated through the inflammatory PG/LT pathways triggered by excitotoxic intracellular calcium excess. These free radicals can damage or destroy virtually every cellular biomolecule: proteins, fatty acids, phospholipids, glycoproteins, even DNA, leading to cell injury or death (1-3, 16, 17). Free radicals are also inevitably formed whenever mitochondria produce ATP (22). Reduced intraneuronal antioxidant defences is a routine finding in autopsy studies of brains from Alzheimer's and Parkinson's patients (2). Although vitamins C and E are the two most important nutritional antioxidants, and brain cells may concentrate C to levels 100 times higher than blood levels (30), antioxidants work as a team. Free radical researcher Lester Packer has identified C, E, alpha-lipoic acid, CoQ10 and NADH as the most important dietary antioxidants (31,32). Idebenone has also shown great power in protecting various types of neurons from free radical damage and other excitotoxic effects. Idebenone is able to protect neurons at levels 30-100 times less than the vitamin E levels needed to protect neurons from excitotoxic damage (33-37). One of the many ways excitotoxins damage neurons is to prevent the intracellular formation of glutathione, one of the most important cellular antioxidants. The combination of E and Idebenone provided complete antioxidant neuronal protection in spite of extremely low glutathione levels caused by GLU excitotoxic action (33,34). Idebenone has also shown clinical effectiveness in treating various forms of stroke and cerebrovascular dementia, known to be caused by excitotoxic damage (38).
Deprenyl is also indicated for prevention of excitotoxic free radical damage. In a recent study, Mytilneou and colleagues showed that deprenyl protected mesencephalic dopamine neurons from NMDA excitotoxicity comparably to the standard NMDA blocker, MK-801 (39). The chief bodily metabolite of deprenyl, desmethylselegeline, was shown to be even more powerful than deprenyl itself at preventing NMDA excitotoxic damage to dopamine neurons (40). Maruyama and colleagues showed that deprenyl protected human dopaminergic cells from apoptosis (cell suicide) induced by peroxynitrite, a free radical generated through NMDA excitotoxic action (3,17). Deprenyl has also been shown to significantly increase the activity of 2 key antioxidant enzymes, superoxide dismutase (SOD) and catalase, in rat brain (41). There is also good evidence that deprenyl, through its MAO-B inhibiting action, may favourably modulate the polyamine binding site on NMDA receptors, thereby reducing excitotoxicity (41). A basic anti-excitotoxic antioxidant program would thus consist of the following: 200-400 IU d-alpha tocopherol; 100-200 mg gamma tocopherol (this form of vitamin E has recently been shown to be highly protective against peroxynitrite toxicity, unlike d-alpha E (42)); 100-200 mcg selenium as selenomethionine (selenium is necessary for the activity of glutathione peroxidase, one of the most critical intracellular antioxidants); 500-1,000 mg vitamin C 3-5 times daily; 50-100 mg alpha-lipoic acid 2-3 times daily; 50-300mg CoQ10; 5-20 mg NADH (empty stomach); 45 mg Idebenone 2 times daily; 1.5-2 mg deprenyl daily. Note that some of these are already covered by the energy enhancement program.
Zinc is necessary for one form of SOD - zinc SOD - and also blocks the NMDA receptor. However, high levels of neuronal zinc may over activate the quisqualate/AMPA GLU receptors, causing an excitotoxic action (1,2). Dr Blaylock, the neurosurgeon author of Excitotoxins (2), therefore recommends keeping supplementary zinc levels to 10-20 mg daily (2).
5) Inadequate removal of extracellular (synaptic) GLU. Excessive synaptic GLU/ASP will keep GLU receptors (NMDA or non-NMDA) overactive, promoting repetitive neuronal electrical firing, calcium/sodium influx, and resultant excitotoxicity. Avoiding dietary MSG/ASPTM will help to minimize synaptic GLU/ASP levels. Keeping neuronal ATP energy maximal through avoidance of hypoglycaemia (i.e. don't skip meals or practice "starvation dieting"), combined with the supplemental energy program described in 1) above, will promote adequate ATP to assist GLU pumps to remove excess extracellular GLU to astrocytes. Adequate ATP will also promote astrocyte conversion of GLU to glutamine, the chief GLU removal mechanism. Adequate ATP will also keep calcium and sodium pumps active, preventing excessive intracellular calcium build-up. Intracellular calcium excess itself promotes renewed secretion of GLU into synapses, in a positive feedback vicious cycle (3).
An enzyme called "GLU dehydrogenase" (GDH) also helps neurons dispose of excess GLU by converting GLU to alpha-ketoglutarate, a Krebs' cycle fuel. GDH is activated by NADH, so taking the NADH recommended in the energy and antioxidant programs will also promote breakdown of GLU excess. Excessive levels of free radicals has been shown to inhibit GLU uptake by astrocytes, the major route for terminating GLU receptor activation (29), so following the antioxidant program will also aid in clearing excess synaptic GLU.
In order to maximize clearance of synaptic GLU, it will also be necessary to avoid use of the nutritional supplement glutamine (GAM). The health food industry has promoted GAM use for decades, often in multi-gram quantities. A 1994 book touts GAM "to strengthen the immune system, improve muscle mass, and heal the digestive tract" (43). It is true that many studies do show benefits form short-term, often high dose, GAM use. It must be remembered, however, that GAM easily passes the BBB and enters the astrocytes and neurons, where it can be converted to GLU. And the excitotoxic damage from excess GLU may take a lifetime to develop to the point of expressing itself as a stroke, Alzheimer's or Parkinson's disease, etc. But high dose GAM can cause excitotoxic problems even in the short term. At last year's Monte Carlo Antiaging Conference ™, I met a man who routinely consumed 20 grams of GAM daily. He suffered extremely severe insomnia, nervousness, anxiety, racing mind, and other symptoms of excessive GLU neurotransmission. GAM supplementation should probably not exceed 1-2 grams daily, if it is used at all.
A 1994 review article referred to excitotoxicity as "the final common pathway for neurologic disorders" (3). Yet public awareness of the excitotoxic phenomenon has been slow in coming, even in the life extension/natural medicine/health food communities. Only one book has tried to alert the public to the details of how excitotoxins gradually (or sometimes suddenly) destroy our brains: Blaylock's 1994/1997 Excitotoxins (2). This article has barely scratched the surface of excitotoxins and their role in our lives. The interested reader is strongly urged to read Blaylock's book. It is written by a neurosurgeon, is highly readable and understandable for such a technical subject, and provides a wealth of practical information and extensive scientific documentation. Blaylock presents an especially detailed picture of the role of GLU/ASP excitotoxicity in the development of Alzheimer's disease, as well as steps to prevent or cope with Alzheimer's. It makes little sense to pursue other anti-aging strategies, such as growth hormone, testosterone or estrogen replacement, cardiovascular fitness exercise, weight loss, etc. while not doing everything possible to avoid excitotoxicity. As Blaylock points out, in a recent survey of the elderly, it was learned that the incidence of Alzheimer's was 3% among the 65 to 74 age group, 18.7% among those 75 to 84, and 47.2% (!) among those 85 and older (2). The over 85 age group is the fastest growing age group in the U.S. Anyone who seriously follows the anti-aging techniques promoted by IAS, VRP or LEF has a real chance of joining that 85-plus age group. But what is the point of reaching 85, only to end up suffering the terrible physical, mental and emotional deterioration of Alzheimer's (or Parkinson's, or stroke dementia, etc.)?
Learning about, and doing what is necessary to cope with, the brain's tendency to excitotoxically "melt down" is the best brain anti-aging insurance available.
1) Choi, D. (1988) "Glutamate neurotoxicity and diseases of the nervous system" Neuron 1: 623-34.
2) Blaylock, R. Excitotoxins. Santa Fe: Health Press, 1997.
3) Lipton, S. & Rosenberg, P. (1994) "Excitatory amino acids as a final common pathway for neurologic disorders" NEJM 330: 613-22.
4) Greenamyre, J. & Porter, R. (1994) "Anatomy and physiology of glutamate in the CNS" Neurol 44: s7-s13.
5) Braverman, E. et al. The Healing Nutrients Within. New Canaan: Keats Pub., 1997.
6) Roberts, H. Aspartame (NutraSweet ®) Is It Safe? Philadelphia: The Charles Press, 1990.
7) Blaylock. R. (2000) "Excitotoxins: Dangerous Food Additives" Nexus 7 (#4&5), 31-34, 74-75 & 35-40.
8) Whetsell, W. & Shapira, N. (1993) "Biology of disease. Neuroexcitation, excitotoxicity and human neurological disease." Lab Invest 68: 372-87.
9) Olney, J. (1989) "Glutamate, a neurotoxic transmitter" J Child Neurol 4: 218-26.
10) Olney, J. et al (1997) "Excitotoxic neurodegeneration in Alzheimer disease" Arch Neurol 54:1234-40.
11) Tsai, G.E. et al (1998) "Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal" Am J Psychiat 155: 726-32.
12) (2001) "Needless brain wasting" Life Extension 7 (7): 64-68.
13) Blaylock, Excitotoxins, p.49.
14) Levitan, I. & Kaczmarek. The Neuron. NY & Oxford: Oxford Univ. Press, 1997.
15) Guyton, A. & Hall, J. Textbook of Medical Physiology. Philadelphia: W.B. Saunders, 2000.
16) Levine, S. & Kidd, P. Antioxidant Adaptation. S.F.:Biocurrents, 1986.
17) Maruyama, W. et al (1998) "(-)-Deprenyl protects human dopaminergic neuroblastoma Écells from apoptosis induced by peroxynitrite and nitric oxide" J Neuronchem 70: 2510-15.
18) Sorg, O. et al (1997) "Inhibition of astrocyte glutamate uptake by reactive oxygen species: role of antioxidant enzymes" Mol Med 7: 431-40.
19) Pol, A. et al (1990) "Glutamate, the dominant excitatory transmitter in neuroendocrine regulation" Sci 250: 1276-78.
20) Toth, E. & Lajtha, A. (1981) "Elevation of cerebral levels on nonessential amino acids in vivo by administration of large doses" Neurochem Res 6:1309-17.
21) Zaloga, G. (1990) "Physiologic effects of peptide-based enteral formulas" Nutr Clin Pract 5: 231-37.
22) South, J. (1999) "Tired of being tired?" Anti-Aging Bull 4(4): 3-21.
23) Wester, P.o. (1987) "Magnesium" Am J Clin Nutr 45: 1305-12.
24) Seelig, M. (1964) "Perspectives in nutrition. The requirement of magnesium by the normal adult" Am J Clin Nutr 14: 342-90.
25) South, J. (1990) "Magnesium: the missing link to health" Opt Nutr Rev 1: 1, 5-8.
26) Newmark, T. & Schulick, P. Beyond Aspirin. Prescott A2: Hohm Press, 2000.
27) Pace-Asciak, C. et al (1995) "The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: Implicaitons for protection against coronary heart disease" Clin Chim Acta 235: 207-19.
28) Kimura, Y. et al (1985) "Effects of stilbenes on arachidonate metabolism in leukocytes" Biochim Biophys Acta 834: 275-78.
29) Same as ref. 18.
30) Grünewald, R. (1993) "Ascorbic acid in the brain" Brain Res Rev 18: 123-33.
31) Packer, L. & Colman, C. The Antioxidant Miracle. NYC: John Wiley, 1999.
32) Packer, L. & Tritschler, H. (1996) "Alpha-lipoic acid: the metabolic antioxidant" Free Rad Biol Med 20: 625-26.
33) Oka, A. et al (1993) "Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms and protection" J Neurosci 13: 1441-53.
34) Murphy, T. et al (1990) "Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake" FASEB J 4: 1624-33.
35) Miyamoto, M. & Coyle, J. (1990) "Idebenone attenuates neuronal degeneration induced by intrastriatal injection of excitotoxins" Exp Neurol 108: 38-45.
36) Miyamoto, M. et al (1989) "Antioxidants protect against glutamate-induced cytotoxicity in a neuronal cell line" J Pharmacol Exp Ther 250: 1132-40.
37) Bruno, V. et al (1994) "Protective action of idebenone against excitotoxic degeneration in cultured cortical neurons" Neurosci Lett 178: 193-96.
38) Sekimoto, H. et al (1985) "Efficacy and safety of CV-2619 (idebenone) in multiple cerebral infarction, cerebrovascular dementia, and senile dementia" Ther Res 2:957-72.
39) Mytilineou, C. et al (1997) "L-Deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro" J Neurochem 68: 33-39.
40) Mytilineou, C. et al (1997) "L-(-)-Desmethylselegeline, a metabolite of selegeline [L-(-)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro" J Neurochem 68: 434-36.
41) Gerlach, M. et al (1996) "Pharmacology of selegeline" Neurol 47 (suppl 3): s137-s145.
42) Christen, S. et al (1997) "Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha tocopheral: physiologic implications" Proc Natl Acad Sci USA 94: 3217-22.
43) Shabert, J. & Ehrlich, N. The Ultimate Nutrient Glutamine. Garden City Park, NY: Avery, 1994.