Galantamine—A Very Big Deal
Galantamine Protects Neurons and Memory Following Brain Injury
It improves impaired spatial memory in gerbils,
even when given 3 hours after a simulated stroke
By Lane Lenard, Ph.D.
What a waste it is to lose one’s mind. Or not to have a
mind is being very wasteful. How true that is.
— Dan Quayle
ell, we know what Mr. Quayle meant—sort of. (But did he?) The loss of brainpower with advancing years is one of the most devastating and terrifying aspects of aging. It can destroy lives, not only of those afflicted, but also of their loved ones, who are usually the primary caregivers. The tragedies are heart-rending.
When the heart starts to cause problems, medical science can marshal an impressive array of medications, devices, and procedures to keep it beating for years or even decades longer. In extreme cases, a diseased heart can sometimes be replaced by a transplanted healthy heart. The same can be done for diseased lungs, kidneys, livers, and various other organs and tissues. And when major joints, such as the hips and knees, wear out, they can often be replaced with artificial ones made of high-tech materials.
How Do You Fix an Ailing Brain?
But what to do when our brains start to go? Memories fade, other cognitive functions are impaired, and muscle control suffers—immediately, following a stroke, and more slowly in people with Alzheimer’s disease or other forms of progressive dementia, such as Lewy body dementia and vascular dementia (the second and third most common types of dementia, respectively).
Cerebral bypass surgery? Impossible. Brain transplants? The stuff of science fiction. Clot-busting drugs? They’re potentially useful if administered intravenously within a few hours after a serious stroke, but they can’t help prevent progressive dementias resulting from transient ischemic attacks (“ministrokes”) or the neurodegeneration of Alzheimer’s or Lewy body dementia. Most prescription antidementia drugs are marginally effective, at best, for preserving cognitive function (usually only for a period of months), but they do little or nothing to retard the deterioration of brain cells.
Galantamine Can Help
Enter galantamine, a safe and effective natural chemical compound that has been documented in many scientific studies (in both animals and humans) to put the brakes—temporarily, for periods of up to about one year—on the cognitive decline associated with Alzheimer’s disease and several other types of dementia. Although it’s now sold as a drug called Razadyne, galantamine was used in folk medicine in Eastern Europe for millennia and is still available as a nutritional supplement in the USA.
Modern science has determined that galantamine helps to preserve and protect memory and other aspects of cognition by facilitating our cholinergic function—those aspects of brain function that depend on the neurotransmitter acetylcholine (ACh). A decline in cholinergic function—whether through inadequate amounts of ACh or inadequate responsiveness of neurons (brain cells) to ACh—is the neurophysiological hallmark of Alzheimer’s disease, and it’s characteristic of some other forms of dementia as well. It leads eventually to the wholesale death of neurons and, ultimately, to the patient’s death.
Hello? Acetylcholine Calling . . . How’s the Reception?
Galantamine accomplishes its rescue mission in two ways. One is by acting as an inhibitor of acetylcholinesterase, the enzyme whose function is to destroy excess acetylcholine molecules in the neural synapses, the tiny (one-billionth of an inch) junctions between the transmitting end of one neuron and the receiving end of another. By inhibiting the destroyer of ACh, galantamine effectively boosts the amount of ACh available for the transmission of nerve impulses. In this, it is like most other anti-Alzheimer’s agents.
But galantamine’s real strength lies in its other mode of action, one that is not shared by the other agents. It involves a certain class of receptor molecules that receive the nerve impulses transmitted by ACh. These protein complexes stud the surface of the receiving ends of neurons and act as tiny molecular “magnets” for ACh molecules. Called nicotinic acetylcholine receptors (they happen to be very sensitive to nicotine as well as to ACh), they play an extremely important role in brain function and in the brain’s very survival.
A major factor in the decline in cholinergic function in Alzheimer’s disease is a deterioration in both the number and the sensitivity (responsiveness) of the nicotinic ACh receptors—and that’s where galantamine comes in. Its molecular interaction with these receptors tends to protect them from deterioration, thereby not only facilitating cholinergic function but also protecting the neurons themselves from deterioration and death. This is called neuroprotection, and it’s a very big deal.*
How to Give a Gerbil a Stroke
A recent study by Spanish researchers has added to our knowledge of how galantamine helps protect cerebral neurons from dying. The study involved adult male Mongolian gerbils in which simulated strokes were surgically induced by ligating (tying shut) both of their carotid arteries with silk sutures for 5 minutes. This deprived their brains of blood and the vital nutrients—oxygen, glucose, etc.—it carries to all cells. Blood deprivation to a given region is called ischemia; here, with the entire brain temporarily deprived of blood, the condition is called transient global cerebral ischemia. (Don’t try this at home.)
The objective was to study the effects of galantamine (injected subcutaneously) on the health of neurons of the hippocampus, a brain region closely associated with memory, learning, and other cognitive functions, in the stroke-afflicted gerbils. A previous study by the same group had shown a neuroprotective effect of galantamine on rat hippocampal slices that were subjected to oxygen and glucose deprivation in the laboratory. Now the researchers were trying the same kind of experiment in live animals.
Galantamine Provides Strong Neuroprotection . . .
Would galantamine be neuroprotective in the gerbils’ brains? If so, to what extent? And by what biochemical mechanism? Based on a large body of prior research, the Spanish team surmised that galantamine’s effects would be attributable to its role as a potentiator of nicotinic ACh receptors. To help establish that, they also used a drug called mecamylamine, which is known to block the action of these receptors very effectively. Thus, if mecamylamine strongly prevented galantamine’s protective effects, it would be a good indication that the mechanism of these effects did indeed involve the nicotinic ACh receptors.
Galantamine preserves spatial memory in gerbils following a simulated stroke. Its effect in the sham-operated animals was not statistically significant, but its effect in the “stroked” animals was. Note how mecamylamine negated this effect. (Adapted from Ref. 1)
And that is exactly what was found. When the gerbils were killed (3 days after the surgery) and their hippocampi examined under a microscope, the researchers saw, first of all, that the effects of the transient global cerebral ischemia in the gerbils that had not received galantamine were devastating: a massive die-off of neurons.* In the gerbils that were treated daily with galantamine, however (starting the day before the surgery and continuing for another 3 days), there was a strong protective effect: most of the neurons survived. When mecamylamine was used together with galantamine, this neuroprotection was erased, supporting the hypothesis regarding the nicotinic ACh receptors.
. . . Apparently Mediated by Nicotinic ACh Receptors
To explore further the mechanism of galantamine’s protective action and mecamylamine’s blocking of it, the researchers performed three histological (cell-component-related) tests: one to detect the presence of fragmented DNA in the hippocampal neurons; one to detect an enzyme, caspase-3, that is implicated in cell death; and one to detect an antioxidant enzyme called superoxide dismutase-2 (SOD-2), whose presence is a sign that harmful free radicals have recently been generated.
In all three cases, the substances in question showed high levels in the hippocampal neurons of gerbils injured by transient global cerebral ischemia, compared with the sham-operated gerbils. In all three cases, galantamine decreased these levels dramatically, indicating powerful neuroprotective effects. And in two of the three cases (DNA fragmentation and SOD-2), mecamylamine strongly suppressed galantamine’s effect, again supporting the hypothesis regarding the nicotinic ACh receptors.
The free radicals mentioned above are generated not by the ischemia but by its aftermath—the reperfusion, when blood flows freely again (as would occur in real life, e.g., when a thrombolytic drug dissolves a clot in a cerebral artery, allowing blood to flow into the affected part of the brain). Reperfusion brings a flood of blood—and oxygen—to oxygen-starved tissues, and the resulting burst of biochemical activity generates torrents of free radicals, far in excess of the norm. The cells respond by generating large amounts of SOD-2 and other antioxidants in order to bring things back under control. Before this can happen, however, serious damage is done to cellular proteins, lipids, and nucleic acids. Together, the damage done by the ischemia and the reperfusion is called ischemia-reperfusion injury.
Galantamine Opens a 3-Hour Window of Opportunity for Memory Protection
Having confirmed galantamine’s neuroprotective effects with the histological tests, the researchers turned to something of more practical interest: functional tests of the gerbils’ spatial memory after ischemia-reperfusion injury, with and without galantamine and mecamylamine. The results, given in terms of a calculated “discrimination index” (the higher the value, the better the memory) were similarly clear and gratifying: the sham-operated animals did well on the test, the injured animals did very poorly, the injured animals treated with galantamine did much better (close to the sham-operated group), and mecamylamine erased galantamine’s effects.
The really remarkable thing about the gerbils’ memory test is that the galantamine was administered not before the ischemia-reperfusion injury, but 3 hours after, and it was able to undo much of the damage that had been done during those 3 hours. This is all the more intriguing because in humans, 3 hours is the therapeutic window of opportunity for effective treatment of acute ischemic stroke with thrombolytic (clot-busting) drugs.
Thus it’s tempting to think that galantamine might have therapeutic value in such patients, perhaps helping to reduce the likelihood of permanent brain damage. One can also speculate that galantamine, if taken daily as a supplement, might help to avert such damage in the event of a stroke. That would be a tremendous benefit.
Galantamine May Help Humans with Vascular Dementia or Stroke
Some caution in interpreting these exciting results is in order, however. The last time we looked, gerbils were not human, so extrapolating the Spanish researchers’ findings to the aging human brain is not a sure thing. Nonetheless, many studies, including clinical trials with humans, point to the conclusion that galantamine offers significant neuroprotection and improves memory and other cognitive functions in people already showing signs of mental deterioration. And galantamine is, after all, approved by the FDA for the treatment of mild to moderate Alzheimer’s disease, which tells you something.
Also telling is the evidence for galantamine’s benefits in improving memory, cognition, behavior, and activities of daily living in patients who suffer from Alzheimer’s disease plus vascular dementia.* These two diseases often go hand in hand, sharing the same outward symptoms. Despite their different origins, they have much in common and are often difficult to differentiate except at autopsy, when it doesn’t do the patient any good.
With regard to vascular dementia, the Spanish authors took an aggressively optimistic view by concluding,
This study shows that galantamine treatment prevented neuronal death and improved spatial memory that was impaired after transient global cerebral ischemia and could therefore benefit patients suffering vascular dementia or stroke.
They recommended that human clinical trials be conducted to verify the therapeutic potential of galantamine when administered to stroke patients after the fact. Let us hope that this will be done soon.
- Lorrio S, Sobrado M, Arias E, Roda JM, García AG, López MG. Galantamine postischemia provides neuroprotection and memory recovery against transient global cerebral ischemia in gerbils. J Pharmacol Exp Ther 2007;322:591-9.
- Sobrado M, Roda JM, López MG, Egea J, García AG. Galantamine and memantine produce different degrees of neuroprotection in rat hippocampal slices subjected to oxygen-glucose deprivation. Neurosci Lett 2004;365:132-6.
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med 1995;333:1581-8.
Dr. Lane Lenard earned his Ph.D. in psychology at Rutgers. He has extensive experience as a medical/science writer in the pharmaceutical and supplement industries. He has written many articles for Life Enhancement and was its editor for several years. He has coauthored numerous books and booklets with Jonathan V. Wright, M.D., and others on various aspects of natural medicine. His next book (with Dr. Wright) is tentatively entitled Bio-Identical Hormone Replacement for Women Over 45.