http://www.ana-jana.org/

there is a free pdf from the doctors -I copied this information from -

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

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.

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

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.

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.
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this is a very long list -if anyone wants it in its entirety

go to -dr. blaylocks site

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