EXCITOTOXINS: THE ULTIMATE BRAINSLAYER
By James South
MA
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 &endash; GLU receptors &endash; 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 &endash; the NMDA GLU receptor (more on this later) &endash; 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 &endash; caused
dementia (12).
Experimental NMDA &endash; 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 &endash; 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.
EXCITOTOXICITY 101
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. 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 &endash; 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, 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 &endash;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
&endash;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).
CA: THE EXCITOTOXIC “HIT-MAN”
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!
GLU METABOLISM
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).
EXCITOTOXICITY: THE BACKGROUND FACTORS
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
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).
MSG AND ASPTM: THE HARSH TRUTH
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 &endash; 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 &endash; 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 &endash; 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 &endash; 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.
EXCITOTOXICITY: STEALTH DEVELOPMENT
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.
EXCITOTOXICITY PROTECTION: THE PROGRAM
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 &endash; 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 &endash;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 bodyweight 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).
5) 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.
6) Zinc is necessary for one form of SOD &endash; zinc SOD &endash; 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).
7) 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 Anti-Aging 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.
EXCITOTOXINS: FINAL THOUGHTS AND OBSERVATIONS
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&endash;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.
Copyright 2003. This article may not be reproduced for public
broadcast in any form, without the written permission of: International Antiaging Systems
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