Galantamine Helps Protect Your Neurons

Galantamine’s Dual Mode of Action Is Key

Galantamine Helps Protect Your Neurons
It is this remarkable capability that sets
galantamine apart from other anti-Alzheimer’s agents
By Will Block

First appeared in the April 2005 issue

uman physiology is filled with paradoxes. One form of cholesterol (LDL) is harmful, while another form (HDL) is beneficial. Epinephrine (adrenaline) can help save your life via the fight-or-flight response, or it can kill you by causing a heart attack. Oxygen, the very breath of life, is also highly destructive of life, through oxidative reactions that generate free radicals. Nitric oxide is a free radical that’s corrosive and toxic when breathed as a gas, yet when generated within the body, it’s a neurotransmitter and mediator of reduced blood pressure (and improved erections). Even water can be dangerous in excessive amounts, especially to people with high blood pressure or other cardiovascular problems.

The list seems endless: glucose, homocysteine, the sex hormones, etc. And let’s not forget that the word “pharmaceutical” comes from a Greek word, pharmakon, meaning both “medicine” and “poison.”

There’s No Cognition without Receptors

This one may surprise you: nicotine helps protect against Alzheimer’s disease, and perhaps against other neurological disorders as well. In very low doses, nicotine—a deadly poison that turns out also to be a potent memory- and cognition-enhancing drug—stimulates certain receptors, called nicotinic acetylcholine receptors, in brain neurons.1 (For an explanation of this process, see the sidebar below.)

How Galantamine Does What It Does

Proteins are large, complex molecules that may contain tens of thousands or even hundreds of thousands of atoms. Sometimes several identical or similar protein molecules join to form a large complex whose biological function depends in part on the properties of the complex as a whole and in part on the properties of the constituent proteins (called subunits). Cellular receptors, which are embedded in the cell wall, are an example of such complexes. Typically, their function is to provide a channel designed to allow passage of a particular kind of atom or molecule into or out of the cell—certain metal ions for nerve-impulse transmission, e.g., or glucose molecules for cellular energy metabolism. (For more on this process, see “Galantamine Opens the Channels of Your Memory” in the January 2002 issue.)


Artist’s rendition of a nicotinic acetylcholine receptor (including cutaway view of the ion channel), showing the five protein subunits embedded in the cell wall.
Whether the channel is open or closed at a given instant depends on whether the receptor is being stimulated by the presence of its designated activator molecule (acetylcholine, in the case of cholinergic neurons) or another molecule that has a similar effect (such as nicotine). Stimulation occurs via intermolecular forces at the protein’s binding site, a cavity into which the activator molecule can fit more or less precisely, somewhat like a key in a lock. These interactions cause the protein to change its shape in such a way as to open or close the channel.

In the nicotinic acetylcholine receptor, there are binding sites on the five subunits, of which the a7 subunit is the most critical in terms of neuroprotection, i.e., its frequent stimulation appears to be vital for maintaining the integrity of the neuron. Such frequent stimulation is facilitated by galantamine, which interacts with the a7 subunit (and with others as well) at sites other than the binding sites for acetylcholine. It does this in a way that alters the configuration of the subunit’s binding site, making it more receptive to acetylcholine. This process of indirect potentiation of receptor function is called allosteric modulation.

The picture given here is oversimplified. In reality, receptors are not necessarily static entities whose roles are fixed. Many are highly flexible in various ways. For example, they can increase or decrease in number, they can become more active or less active, and in some cases they can even change their structure and function, becoming receptive to a different neurotransmitter than before.

These receptors are protein complexes embedded in the cell membranes at the synapses, the infinitesimal gaps between neurons, where neurotransmission occurs. They were designed by nature to respond to the neurotransmitter acetylcholine (ACh), which carries neural impulses across the synapses, but they respond to nicotine as well—hence their ominous name.

The other category of acetylcholine receptors, called muscarinic acetylcholine receptors, is named, oddly enough, for another extremely toxic compound, muscarine, which is found in certain mushrooms and in decaying flesh. How strange that the two types of acetylcholine receptors are named for poisons that are beneficial in trace amounts.

Nicotine—One Virtue, Countless Dangers

Our interest here, however, is in the nicotinic acetylcholine receptors (nAChRs for short), which play a key role in maintaining and protecting the brain’s cholinergic system. That’s the system of neural circuits that depends on acetylcholine as its principal neurotransmitter; it’s centrally involved in cognitive functions such as learning and memory.

Thus, by stimulating the receptors that bear its name, nicotine does good. It’s probably the only good thing that nicotine does for us, though. Considering the dozens of dreadful things that smoking does on the other side of the ledger, it would be insane to smoke for the sake of this one benefit. It would be like cutting your head off to lose weight—effective, but a good example of the law of unintended consequences.

What Does Galantamine Do?

Fortunately for you and your head, there is another substance that stimulates nAChRs, and its effects on the human body are entirely on the positive side of the ledger.* This substance is the memory-enhancing nutritional supplement galantamine, a compound extracted not from the noxious tobacco plant but from pretty flowering plants, such as the snowdrop, daffodil, and spider lily. Not that coming from flowers is any guarantee of virtue (some flowers are poisonous), but it’s a nice thought.


*We’re not counting side effects that may be annoying but that do no harm. Galantamine can cause minor gastrointestinal upsets before the body becomes used to it, but these can usually be avoided by starting with a small amount and building up to the full amount gradually over a period of weeks, a practice called dose escalation.



Figure 1. Simplified diagram showing how galantamine’s biological effects lead to significant protection for neurons of the brain’s cholinergic system. The various features shown here are discussed in the text. Galantamine’s strong stimulation of nicotinic acetylcholine receptors—the a7 subunit in particular—sets it apart from other anti-Alzheimer’s agents and makes it effective in providing long-term treatment in mild to moderate cases of this disease. (Adapted from Reference 3.)
What galantamine, a potent anti-Alzheimer’s agent, does in the human brain is remarkable and unique. First, like most other such agents, it enhances acetylcholine levels by acting as an acetylcholinesterase inhibitor, i.e., a molecule that inhibits the enzyme (acetylcholinesterase) that causes the breakdown of ACh molecules (see Figure 1). This leads to stimulation of muscarinic acetylcholine receptors and decreased production of a harmful protein, which we’ll get to in a moment.

In addition, however—and here is where it differs from the other agents—galantamine is a strong stimulator (and thus protector) of nicotinic acetylcholine receptors.2 More precisely, it is a strong stimulator of a particular subunit of the nAChR, called the a7 (alpha7) subunit (see sidebar).

How Alzheimer’s Brains Deteriorate

According to the author of a recent review article on the role of galantamine in neuroprotection, scientists believe that frequent stimulation of the a7 subunit is necessary for survival of cholinergic neurons.3 In normal brains, that’s no problem, but in the brains of Alzheimer’s victims, ACh levels are low, and cholinergic function is impaired by the lack of adequate neurotransmission. When the nAChRs are underutilized as a result, they tend to deteriorate and eventually disappear.

This process is hastened by a waxy, neurotoxic protein called amyloid-b (amyloid-beta, also called senile plaque), which forms in certain regions of the brains of Alzheimer’s victims. It’s one of the anatomical hallmarks of the disease, along with neurofibrillary tangles. These degenerative processes cause cellular stress and, eventually, cell death, which accounts for the striking loss of brain matter seen at autopsy in patients with advanced Alzheimer’s disease.

Meshing nicely with this picture is indirect evidence (cited in the review article) for a link between the frequent stimulation of nAChRs and the reduced formation of amyloid-b. For example, postmortem studies of Alzheimer brains have shown that smokers had much less amyloid-b, and higher levels of preserved nAChRs, than nonsmokers—a finding that jibed with those of studies on laboratory mice. Other studies, however, have given conflicting results on whether smoking decreases or increases the risk for Alzheimer’s. The question thus remains open.

Preclinical Evidence for Galantamine

All this information suggests that acetylcholinesterase inhibitors that can also stimulate acetylcholine receptors, especially the a7 subunit of the nAChRs—but without nicotine’s harmful consequences—may have a substantial neuroprotective effect. Foremost among such agents is galantamine, whose reputation as a proven anti-Alzheimer’s agent rests much more strongly on its ability to stimulate the receptors than on its more prosaic role as an acetylcholinesterase inhibitor (its overall efficacy, of course, derives from both factors).3 Galantamine’s role in neuroprotection is summarized in Figure 1.

The author of the review article discussed three lines of preclinical evidence for galantamine’s neuroprotective effects. Following is a summary.

1. Human Brain Cells

In one study with cultured human brain cells called neuroblastomas, galantamine significantly reduced the high rate of cell death caused by exposure to amyloid-b. The researchers noted a substantial increase in the production of a protein, bcl-2, that’s known to play a key role in inhibiting the natural process of apoptosis, or programmed cell suicide. (For more on this study, see “Galantamine Suppresses Brain-Cell Suicide” in the February 2004 issue.)

Another study documented galantamine’s neuroprotective effect against excessive amounts of glutamate, one of the brain’s most prevalent neurotransmitters. Although glutamate is essential for brain function, it can become toxic—lethal, in fact—to neurons if released in excessive amounts, as can be caused, e.g., by amyloid-b formation. (Paradoxically, galantamine itself enhances the release of glutamate—but in safe amounts.)

2. Slices of Rat Brains

Galantamine has been shown to preserve metabolic activity in slices of rat brain affected by reduced levels of the two most important nutrients for mammals: oxygen and glucose. This condition mimics vascular dementia, in which there is inadequate blood flow to the brain owing to cerebrovascular disease. The brain slices were taken from the hippocampus, a structure intimately involved in cognition, learning, and memory.

3. Genetically Altered Mice

Mice that are genetically altered in a certain way have reduced amounts of a protein called nerve growth factor (NGF). This causes a deficit in cholinergic neurons in the basal forebrain and results in impaired cholinergic function, manifested as behavioral memory-related deficits. (Admittedly, mice don’t have a lot to remember—where the cheese is, cats are bad, things like that—but their tiny abilities can be measured in the laboratory.) In medical terms, treatment with galantamine significantly “rescued” the cholinergic deficit in these transgenic NGF-deficient mice by preventing the loss of cholinergic neurons.

In addition, the mice developed deposits of an amyloid-b precursor, called amyloid precursor protein, in the blood vessels of their brains—but galantamine reduced this buildup by 80%. (For more on this study, see “Galantamine Rescues Damaged Brain Cells” in the March 2003 issue.)

Galantamine Prolongs Life

The evidence described above is all well and good, but what about demonstrating galantamine’s neuroprotective effects in human beings? That turns out to be very difficult, but abundant indirect evidence exists in the form of long-term clinical trials on patients with mild to moderate Alzheimer’s disease. The temporary improvement (typically for about 6 months) and delayed decline in these patients effectively buys them time (around 1 to 2 years) and cannot reasonably be explained except in terms of a neuroprotective effect due to stimulation of the brain’s nicotinic acetylcholine receptors. [For discussions of several recent long-term studies, see “Galantamine May Help You Remain a Smart Cookie” (April 2004), “Galantamine Offers Sustained Cognitive Benefits” (December 2004), and the sidebar “Galantamine Buys Time” in the article “Green Tea May Help Prevent Alzheimer’s” (January 2005).]

So don’t smoke, eat your fruits and veggies (that’s always good advice), get plenty of exercise (good for the brain!), and consider taking galantamine to help keep your cholinergic system humming. Your brain will thank itself for being so smart.

References

  1. Levin ED. Nicotinic Receptors in the Nervous System. CRC Press, Boca Raton, FL, 2002.
  2. Samochocki M, Hoffle A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira F, Lubbert H, Albuquerque EX, Maelicke A. Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 2003;305:1024-36.
  3. Geerts H. Indicators of neuroprotection with galantamine. Brain Res Bull 2005;64:519-24.

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.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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