Galantamine Is a Potent NeuroprotectorGalantamine Suppresses
Research opens new horizons in the treatment of
neurodegenerative diseases such as Alzheimer’s
By Will Block
ife 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.
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.
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?*
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.
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.
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.
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.
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.
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. 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 galantamines 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
As readers of Life Enhancement know from the many articles on galantamine published here previously, this marvelous substance—a “gift from the gods”—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.
- 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.
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.
Will Block is the publisher and editorial director of Life Enhancement magazine.