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Galantamine Suppresses
Brain-Cell Suicide
Research opens new horizons in the treatment of Alzheimer’s
by Will Block.
Highly simplified drawing of a neuron. The human brain contains about
100 billion of them, each with as many as 10,000 connections to other
neurons.
Life is full of choices. We can choose where to live and how to make a
living; we can choose our spouse and the number of our children; we can choose
what to eat and drink, how to have fun in our spare time, and what kind of
health care to seek when we get sick. We can even, in this country of nearly
unlimited freedom of choice, choose whether or not we will help protect our
nation by serving in the military. With rare exceptions, however, we do not
choose the time and manner of our death. Instead, we let nature take its
course—while we do our level best to make our life as long and healthy as
possible.
While We Live, Our Cells Live and Die
We are driven by the will to live. That biological imperative is what
makes virtually every creature—in our case, an organism consisting of
about 5 trillion cells having the collective form and function of a
human being—cling tenaciously to life. But what about those cells? When
we die, they all die too, but isn’t it true that during our life, our
cells are constantly dying and being replaced (in most cases) by new
ones?*
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*Some attrition does occur with age, as cells die and are not replaced.
For example, of the roughly 100 billion neurons in the human brain, we
lose—permanently—about 100,000 daily, or close to 2 billion in half a
century. RIP.
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Yes, it’s true. With one exception (the cells constituting the lenses of
your eyes), all your cells die off—in a very strange manner, as you will
see shortly—and are replaced at a rate such that your entire body is
regenerated about every seven years, on average. After any given
seven-year period, therefore, you can look in the mirror, flash a big
smile, and exclaim, “It’s a new me!” (Ironically, though, you’ll be
looking through those same old lenses of yours—unless you’ve had
cataract surgery to replace them.)
Brain Cells May Need a Protector
Lenses aside, the question is: How do our cells die, and why do they
die? There are two ways, but many reasons. As we will see, some of those
reasons are good, serving the best interests of our health, but others
are bad, working to undermine our health. It is especially distressing
when brain neurons (nerve cells) die for the wrong reasons and are not
replaced. A net loss of brain neurons can mean only one thing: a net
loss of brain function.
Although some degree of loss seems to be an inevitable part of the aging
process, we naturally want to prevent it as best we can, especially when
it comes to loss that can be considered pathological, i.e., beyond the
normal bounds due to aging itself. Fortunately for us, some chemical
compounds that are able to cross the blood-brain barrier and gain access
to brain neurons have neuroprotectant properties. One such compound is
the natural nutritional supplement galantamine, which is widely used for
the prevention and treatment of Alzheimer’s disease. Before we get to
that, however, let’s return for a moment to the question of how and why
cells die.
The Good and Bad Sides of Cellular Suicide
One way that cells die is by injury, such as that caused by trauma (a
cut or bruise or burn, e.g.) or by exposure to toxic chemicals. Those
events occur rarely, however. By far the more common mode of death for
cells—and here is where they are dramatically unlike us—is suicide.
That’s right: cells usually die in a manner and at a time of their own
choosing, so to speak. They can’t actually think, of course, but their
own internal genetic machinery (the DNA molecules that constitute their
chromosomes) tells them when to die, in response to a variety of factors
that affect their structure and function. This phenomenon is called
programmed cell death, or, in medical jargon, apoptosis (pronounced
ap-op-TOE-sis). For more on this remarkable phenomenon, see the sidebar.
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A Cell-Suicide Primer
Death is never pretty, but our
natural curiosity makes us want to understand the process. When our
cells die by injury, they characteristically swell up, because the
ability of the cell wall to control the passage of water molecules
and vital metal ions is disrupted. Their contents then leak out into
the surrounding tissues, causing inflammation.
By contrast, when cells die by suicide—apoptosis—they undergo
degradation of their chromosomes and mitochondria; they shrink,
develop blebs (tiny blisters) on their surface, and break into
small, membrane-wrapped fragments, which are then engulfed by other
cells called phagocytes (literally, cell-eating cells). The
phagocytes release proteins called cytokines to inhibit
inflammation.
This genetically regulated process is so orderly that it is called
programmed cell death. It is as intrinsic an element of cellular
function as mitosis, the process of cell division to produce two new
cells. Like mitosis, apoptosis is necessary for the proper
development or functioning of the organism. For example, the
formation of proper connections (synapses) between neurons in the
brain requires that excess cells be eliminated by apoptosis, and the
sloughing off of the inner lining of the uterus (the endometrium) at
the start of each menstrual period occurs by apoptosis.
Much more common, however, is the need to destroy cells that
represent a threat to the organism’s health for one reason or
another. Here are four such threats:
- The cells are infected with viruses (some
of which, in a life-and-death struggle, are able to mount
countermeasures against apoptosis), and are induced to apoptosis
by immune-system white blood cells called cytotoxic T lymphocytes
(CTLs).
- The CTLs themselves have become too
numerous, so they must be removed to prevent them from attacking
body constituents. These cells can induce apoptosis in each other
and even in themselves.
- The cells’ chromosomes have undergone DNA
damage that could cause the cells to disrupt proper embryonic
development (causing birth defects), or to become cancerous. Cells
respond to such a threat by increasing their production of a
protein called p53, which is a potent inducer of apoptosis.
- The cells are cancerous, and radiation
therapy or chemotherapy, if they don’t kill the cells outright,
may cause them to self-destruct through apoptosis.
A cell’s “decision” to commit suicide is determined by the balance
between positive molecular signals—those that are needed for the
cell’s continued survival (such as growth factors for neurons)—and
negative molecular signals—those that say, in effect, that it’s
time for the cell to die. As long as the positive signals
sufficiently outweigh the negative signals, the cell lives; when
the balance shifts to the other side, however, it’s curtains for
the cell.
Among the negative signals that can doom a
cell are: an excessive amount of reactive oxygen species (ROS),
including free radicals, in the cell; damage to the cell’s DNA by
ROS or by other agents, such as ultraviolet radiation, x-rays, or
chemotherapeutic drugs; and certain molecules, called death
activators, that bind to specific receptors on the cell’s surface
and “demand” apoptosis of the cell.
When the cell does undergo apoptosis, it can occur through any of
three different mechanisms. In one mechanism, the signals arise
within the cell (often in response to damage caused by dangerous
ROS) and lead to a chain of events that destroy the cell’s
structural proteins. In the second mechanism, similar signals arise
from external agents, such as CTLs or death activators, leading to
the same result.
The third mechanism, which is quite different, occurs in neurons and
perhaps some other cells, and it too may be triggered by dangerous
ROS. It involves the release of a protein called apoptosis-inducing
factor (AIF) from the mitochondria; AIF migrates into the cell’s
nucleus, where it destroys the DNA, killing the cell.
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Apoptosis is both a good thing and a bad thing. It’s good when it serves
the useful purpose of causing an aged and perhaps increasingly
dysfunctional cell to self-destruct and be replaced by a bright and
shiny new one, full of the vigor of cellular youth. Apoptosis is bad,
however, when it’s induced prematurely or excessively by outside agents
or by physiological processes that have been disrupted in some way and
have gone awry.
A Quick Look at Alzheimer’s Disease
Whoa—that last sentence is not a bad description of Alzheimer’s disease.
Alzheimer’s is characterized by several key features, most notably:
The death by apoptosis of neurons in certain regions of the brain,
especially those involved in cognitive functions such as memory and
learning. There is no current treatment for this progressive, and
ultimately devastating, loss of neurons.
The accumulation, in those regions of the brain, of harmful deposits
(outside the cells) of senile plaque consisting of a gunky, insoluble
protein called beta-amyloid (there’s your “outside agent”). Usually
accompanying the senile plaque is the formation of twisted, knotted
bundles of fibers (inside the cells) called neurofibrillary tangles,
which are also harmful.
The disruption of cholinergic activity (neuronal activity that is
mediated by the neurotransmitter acetylcholine) in those regions of the
brain, causing cognitive functions to deteriorate. This is an early and
consistent neurological feature of Alzheimer’s disease.
In the composite drawing at the bottom, the right half is normal, and
the left half shows the loss of brain matter characteristic of
Alzheimer’s disease.
Not surprisingly, these phenomena are linked: the beta-amyloid, e.g., is
believed to be responsible, in large part, for the degeneration and
death by apoptosis of the affected neurons, which in severe cases can
account for as much as 20% of the brain’s entire mass. At autopsy,
one can see distinct holes where brain matter once was, as well as a
widening of the gaps between the convolutions in the cerebral cortex.
A factor that is believed to underlie much of the brain damage seen in
Alzheimer’s disease is the presence of reactive oxygen species (ROS),
including highly destructive free radicals. That is one reason why it’s
so important to supplement with antioxidants.
Galantamine Protects Cognitive Function
Much research during the past decade has shown convincingly that the
best treatment option for Alzheimer’s disease is galantamine, primarily
because of a unique advantage it holds over the other therapeutic agents
that have been in widespread use (the prescription drugs donepezil and
rivastigmine; tacrine has fallen out of favor because of its severe side
effects). That advantage lies in galantamine’s unique dual mode of
action. Like its therapeutic competitors, it is a potent inhibitor of
acetylcholinesterase (the enzyme that causes the depletion of
acetylcholine levels), thus tending to boost the brain’s acetylcholine
levels.
Unlike its competitors, however, galantamine is also a potent modulator
of nicotinic acetylcholine receptors on brain neurons; these crucial
receptors are found predominantly in regions of the brain, such as the
hippocampus, that are associated with memory and other cognitive
functions. Galantamine acts to stimulate their production, protect them
from degradation, and make them more receptive to neurotransmission by
acetylcholine molecules. The significance of these actions is great
indeed, not only because they add another level of protection of
cognitive function in existing neurons, but also because they provide a
biochemical avenue by which the neurons themselves can be protected from
death by apoptosis.
Galantamine Suppresses Apoptosis
A group of researchers from Spain and Brazil recently undertook to
determine whether galantamine could prevent apoptosis in neurons in
laboratory experiments.1 The cells they used were taken
from cows and humans; in the latter case, they were neuroblastoma cells
(a neuroblastoma is a malignant tumor composed of embryonic cells from
which neurons develop). The agents used to promote apoptosis in these
cell cultures were beta-amyloid and a toxic, tumorigenic chemical
compound, thapsigargin, which is a known death activator (see the
sidebar above for an explanation of this term).
When the researchers treated the neurons with galantamine in
concentrations similar to those that occur in the human body in clinical
practice, they found that it had a potent antiapoptotic action in the
bovine cells and the human neuroblastoma cells. In the case of apoptosis
induced by beta-amyloid in the neuroblastoma culture, the proportion of
apoptotic cells without galantamine treatment was 24%, and with
galantamine it was reduced to only 8%.
For purposes of comparison, the researchers tested the anti-Alzheimer’s
drug tacrine in the same manner. Despite its being a stronger inhibitor
of acetylcholinesterase than galantamine, tacrine showed no
neuroprotective effect at all. This and various other lines of evidence
led to the conclusion that galantamine’s neuroprotective effect is very
probably unrelated to its action as an acetylcholinesterase inhibitor.
Rather, the effect is almost certainly due to its action on the
nicotinic acetylcholine receptors—the feature that distinguishes
galantamine from other anti-Alzheimer’s agents.
Galantamine’s Neuroprotection Can Help Fight Alzheimer’s Disease
In addition to these results, the researchers found that galantamine
produced a mild and sustained elevation of calcium levels in the cells,
a condition that is known to favor neuronal survival (too much calcium,
however, can wreak havoc by unleashing torrents of free radicals that
will kill neurons). And they found that galantamine elevated the levels
of a protein called Bcl-2, which is a known antiapoptotic agent, i.e.,
the opposite of a death activator. In the bovine cells, the levels of
Bcl-2 were doubled, and in the human neuroblastoma cells, they were
tripled.
The researchers suggest that their results may help explain the
well-documented beneficial effects of galantamine on cognitive function
and behavior in Alzheimer’s patients. They go on to say:
Furthermore, the neuroprotective effects shown here could explain the
long-term beneficial effects of galantamine on cognition and daily
function for 1 year, 3 years, or even for 4 years. . . . Since apoptosis
seems to be the underlying mechanism of neuronal death in patients
suffering Alzheimer’s disease, in addition to improving cognition by
facilitating cholinergic neurotransmission, galantamine could behave as
a neuroprotective drug to modify the course of Alzheimer’s disease. Our
findings trace a new line of research in looking for new therapeutic
targets and for drugs with neuroprotective properties, to treat
neurodegenerative diseases.
It Makes Sense to Choose Galantamine
Galantamine is available as a safe and effective nutritional supplement
in the United States, without the need for a prescription, even though
it is also sold by prescription (and at much higher cost) as Reminyl®.
For those who wish to preserve and protect their precious memory and
cognition naturally against the insidious incursions of age-related
cognitive impairment, the choice is clear: they can choose life
enhancement through supplementation, in the form of galantamine.
Reference
1. Arias E, Alés E, Gabilan NH, Cano-Abad MF,
Villarroya M, García AG, López MG. Galantamine prevents apoptosis
induced by beta-amyloid and thapsigargin: involvement of nicotinic
acetylcholine receptors. Neuropharmacology 2004;46:103-14.
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Dual-Action Galantamine
Galantamine provides a heralded dual-mode
action for boosting cholinergic function: it inhibits the enzyme
acetylcholinesterase, thereby boosting brain levels of
acetylcholine, and it modulates the brain's nicotinic receptors so
as to maintain their function. The recommended daily serving ranges
from a low of 4 to 8 mg of galantamine to begin with to a maximum of
24 mg, depending on the individual's response.
For an added measure of benefit, it is a good idea to take choline,
the precursor molecule to acetylcholine, as well as pantothenic acid
(vitamin B5), an important cofactor for choline. Thus it is possible
to cover all bases in providing the means to enhance the levels and
effectiveness of your acetylcholine.
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