Galantamine Hits a Triple
A New Window on Galantamine's Benefits
Galantamine’s dual-mode action on Alzheimer’s disease may be triple-mode instead
By Will Block
wise man (it might have been Art Linkletter) once suggested that, when you’re introduced to a small child who’s shy with strangers, a good way to break the ice is to ask, “Have you ever been stung by a bee?” Chances are, the child will light up and start talking, and you’re in.
You should, of course, be prepared with your own bee story—but probably not the one that follows, which only the most precocious tykes would appreciate. It’s not really about bees anyway, but about a particular neurotoxin found in bee venom, called apamin. Neurotoxic compounds isolated from the venoms of various insects, spiders, scorpions, snakes, shellfish, etc., are of inestimable value to neuroscientists, because they affect our neurons in ways that illuminate many important aspects of the physiology and molecular biology of the nervous system, both central and peripheral.
Low-resolution computer-graphic image (end view) of an ion channel; the colors are artificial.
Apamin is known for its ability to block the action of something called the small-conductance calcium-activated potassium channel, which we’ll call SK for short (because that’s what many scientists call it and because even SCCAPC is too long). The SK is an example of an ion channel, a molecular device for facilitating the transport of specific ions or small molecules through cell walls, from the outside to the inside or vice versa.
Ion Channels Carry the Currents of Life
More specifically, an ion channel is a protein molecule or a small cluster of closely related protein molecules embedded in the cell wall, with a slender channel, or pore, that runs down the middle, from the outside of the cell to the inside. Many ion channels act as receptors, meaning that they respond in some specific way to a particular kind of molecule when that molecule binds chemically to a special site on the receptor surface. Cell walls are studded with countless ion channels and other kinds of receptors.
The importance of ion channels to life processes could hardly be overstated, because the latter depend so critically on the cellular inflow and outflow of ions such as sodium, potassium, calcium, chloride, and bicarbonate, and of molecules such as glucose and numerous amino acids. Ion fluxes (electrochemical currents), for example, make muscle contractions, heartbeats, and nerve impulses possible. Ion fluxes are the nerve impulses, in fact, along with neurotransmitter molecules, such as acetylcholine, which allow the currents to jump the synaptic junctions between one neuron and the next, or between a neuron and a muscle cell.
Two crucial features of ion channels are: (1) they are selective for certain ions or molecules (admitting no others), and (2) they can open and close so as to control the flow of ions; this is called gating. For example, each time a sodium-ion channel opens—for about 1 millisecond at a time, hundreds of times per second—about 7000 ions zip through it—in single file! The research that led to a detailed understanding of the workings of ion channels at the atomic level led to the 2003 Nobel Prize in chemistry for Roderick MacKinnon of Rockefeller University.
How a Neurotoxin Can Improve Your Memory
True to their fearsome name, neurotoxins are harmful to our nervous system, and many are fatal even at low levels. Paradoxically, though, these same compounds can sometimes be beneficial at very low levels and under the right circumstances. Apamin, for example, accelerates spatial and nonspatial memory encoding in a region of the mouse brain called the hippocampus, which is strongly associated with memory and learning, and it improves learning and object-recognition tasks in rats. What goes for mice and rats probably goes for people too.
Apparently apamin increases excitability (in the electrical sense) and facilitates synaptic plasticity (the ability of neuronal connections to change strength) of hippocampal neurons. Such neurological enhancements would be especially beneficial to patients with Alzheimer’s disease, in whom the brain region most heavily damaged is the hippocampus.
Galantamine’s Dual Mode of Action
Apamin’s action is attributed to its blockage of the SK, i.e., its blockage of the flow of potassium ions (K) in that particular kind of channel (there are many other kinds of potassium channels). This discovery led a group of researchers from Spain and Italy to test another compound—a plant alkaloid derived from various flowers—to see whether it might also block the SK. The compound was galantamine, which is currently the premier therapeutic agent for the treatment of mild to moderate Alzheimer’s disease. Galantamine is well known for its unique, dual mode of action:
As an acetylcholinesterase inhibitor, galantamine interferes with the action of acetylcholinesterase, an enzyme that continually destroys “used” acetylcholine (ACh) molecules in the synapses while new ones are being made for the next nerve impulse. Galantamine thus tends to enhance synaptic ACh levels, a desirable result in Alzheimer’s disease, in which ACh levels are depleted by neuronal decay.
- As an allosteric potentiating ligand for nicotinic acetylcholine receptors (don’t sweat the jargon), galantamine binds to a certain class of ACh receptors, making them more responsive to ACh and thus enhancing ACh’s potency as a neurotransmitter. The receptors are named for nicotine because of their exceptional responsiveness to this deadly neurotoxin, which, in tiny amounts, improves neuronal function and hence cognitive function. (Don’t even think about smoking—it will kill you.)
Could There Be a Third Mode of Action?
It’s primarily the second of these mechanisms that makes galantamine so effective in treating Alzheimer’s disease and its common precursor condition, mild cognitive impairment. Galantamine attaches itself to the nicotinic ACh receptors at a site other than that where ACh attaches. The receptors (which are at the ends of sodium-ion channels) then become more responsive to ACh, and their efficiency in propagating the nerve impulses that ACh “neurotransmits” is improved.
Galantamine is also known to enhance the release of various other neurotransmitters, and the Spanish and Italian researchers had preliminary evidence that it could enhance the K-induced release of the catecholamines adrenaline and noradrenaline. For reasons too technical to discuss here, this suggested that galantamine’s beneficial effects might be due to yet a third mechanism, namely, the blockade of SK, an action that is known from several studies to increase neurotransmitter release and to enhance memory and learning.
Galantamine’s Cognitive Benefits May Be
Due in Part to Blockade of SK
For their experiments, the researchers chose rat chromaffin cells, which are found in the medulla of the adrenal glands and are rich in catecholamines. These cells share with neurons a common embryological origin, and they have similar structural and functional features, including excitability (the ability to be stimulated to create electrochemical currents) and the ability to store chemical mediators, such as neurotransmitters and hormones. Chromaffin cells have nicotinic acetylcholine receptors and various types of K channels, including SK.
Using both apamin and galantamine (separately) in their electrophysiological study, the researchers found that both substances provided selective inhibition of SK (a calcium-activated potassium channel), resulting in the enhanced release of catecholamines induced by acetylcholine and high potassium-ion concentrations, independently of the increase in calcium ions mediated by calcium channels. (It’s too complicated to explain.) The authors stated,
Brain K channels play an important role in regulating learning and memory processes. . . . one is tempted to think that blockade of KCa2 channels [SK] by galantamine could explain, at least in part, some of its well documented benefits on cognition, behavior, and function of patients suffering from Alzheimer’s disease or vascular dementia.
The experiments do not, of course, prove this hypothesis, nor do they suggest, in any case, what proportion of galantamine’s benefits may be due to its selective inhibition of these potassium-ion channels. But it’s a start.
To Bee or Not to Bee?
Have you ever been stung by a bee? If so, it might amuse you to realize, in retrospect, that the venom that caused you pain may also, briefly, have given your cognitive functions a bit of a boost. To really sharpen your wits, you could try wading naked into a swarm of bees, waving your arms wildly. Or, if you’re just too lackluster a person to do that, you could try taking galantamine, whose dual mode of action may just have graduated to a triple mode. Three cheers for galantamine!
- Alés E, Gullo F, Arias E, Olivares R, García AG, Wanke E, López MG.
Blockade of Ca-activated K channels by galantamine can also contribute to the potentiation of catecholamine secretion from chromaffin cells. Eur J Pharmacol 2006;548(1-3):45-52.
Will Block is the publisher and editorial director of Life Enhancement magazine.