A rescue for the mind

Galantamine Keeps Neurons Alive
It is astounding that the ancient world knew of a plant’s abilities
to heal the mind and remedy Alzheimer’s-like memory loss
By Will Block

Here [says Hermes to Odysseus],
take this potent herb,
and go to
the house of Circe
[the sorceress, who has drugged Odysseus’s crew],
and it shall ward off from
thy head the evil day.

And I will tell thee
all the baneful wiles of Circe.
She will mix thee a potion,
and cast drugs into the food;
but even so she shall not
be able to bewitch thee,
for the potent herb that
I shall give thee will not suffer it.


— Homer, The Odyssey, Book X


Circe Invidiosa by John William Waterhouse, 1892
hat Hermes, the messenger of the Gods, is talking about in the above passage—found in the great epic tale of the Mediterranean—is moly, which has been identified as the plant Galanthus nivalis, the source of the memory phytonutrient galantamine. It is astounding that the ancient world knew of this plant’s abilities to heal the mind and remedy Alzheimer’s-like memory loss—Circe’s victims had forgotten their loved ones, their homeland, their mission, and even who they themselves were. And to prove galantamine’s merit, Homer chose to weave this memory herb into the fabric of the tales selected to represent what is worth remembering about prehistory. Recall that Odysseus is the champion of memory and the enemy of forgetfulness. He is also the hero who rescues us from the fog that prevents us from retrieving what we need to know in order to act confidently and wisely. And also enabling us to steer our course—not merely across the dark sea of Odysseus—but into an unknown future.

Pushing the Right Buttons

Imagine an individual who begins life with Alzheimer’s disease and instead of progressing further into degeneration, grows to revitalize the tools of memory, to claim the youthfulness of recollection, and to become mentally virile. Such an idea was the basis for a short story by the redoubtable F. Scott Fitzgerald, about a man born at what normally would be the end of his life. This man, instead of growing older, grows younger and thus has the rare opportunity of living his life in reverse. While Fitzgerald is said to have thought less of this work, despite the small space of its format, the story is profound, and an unusual feed into what is hailed by many as the best picture of 2008. Starring Brad Pitt and Cate Blanchett, The Curious Case of Benjamin Button is masterful and timely, especially appearing in the midst of the crisis that currently grips the world, at a time when we need tales of great passion, insight, and courage. What if you could push the right “button” and restore yourself to full cognitive health or, further yet, enhance yourself in ways that would make you an even more curious case than Benjamin Button?

Galantamine Preserves Spatial Memory Following Stroke

In the fall of 2007, we reported on a paper finding that galantamine was able to protect neurons and memory following brain injury, improving impaired spatial memory in gerbils, even when given 3 hours after a simulated stroke. (See “Galantamine Protects Neurons and Memory Following Brain Injury” in the September 2007 issue.)

Now, a new study from the same Spanish research group has found that galantamine appears to be beneficial in ways that supersede the benefits of the late-stage Alzheimer’s drug memantine.1 In the study, memantine did not exert a clear neuroprotective effect, nor did it prevent spatial memory loss in gerbils following an induced stroke, although galantamine did. Also just reported in another paper, galantamine’s benefit range has now been extended from the mild and moderate to the severe stages of Alzheimer’s disease (see the sidebar, “Galantamine Helps Severe Alzheimer’s Disease”), so it is now encroaching on memantine’s turf. Not bad for an herbal extract.

Galantamine Helps Severe Alzheimer’s Disease

Galantamine has been shown to be effective in patients with mild, moderate, and advanced moderate Alzheimer’s disease (AD). In a recent paper, for the first time, researchers report benefit in patients with severe AD.1 Patients in a nursing home setting with an average age of 84—81% of whom were women—who were evaluated to have severe AD (a test called the mini-mental state examination made the determination), were randomly assigned to receive either 24 mg/day of galantamine, or placebo. There were 207 in the test group, and 200 in the control group.

The researchers measured both cognitive function and the ability to undertake normal daily activities. They monitored adverse events, vital signs, laboratory parameters, and electrocardiograms. Of those who completed the study, Severe Impairment Battery (SIB) scores increased (improved) by 1.9 to 3.9 points with galantamine and decreased (worsened) by 3.0 points with placebo. SIB estimates the cognitive aptitudes and other skills of severely impaired dementia patients in order to analyze the relationships between the different cognitive domains and their loss of autonomy. Memory, movement, and visuospatial ability improved nominally in those taking galantamine, while self-performance score worsened by 1.2 points and 1.6 points, respectively in galantamine and placebo groups.

Side effects were similar in both groups, which were mostly mild to moderate. Not conclusive, but interesting, eight patients (4%) in the galantamine group and 21 patients (11%) in the placebo group died. ECG abnormalities were similar between the two groups. The researchers interpreted the results by stating:

Galantamine can be started and used safely in elderly patients with severe AD. Galantamine improved cognitive function but failed to significantly improve the co-primary parameter of overall activities of daily living . . . . The results are consistent with those previously reported, and extend the efficacy range from patients with mild to moderate and advanced moderate into severe AD.

Also of consequence, it was noted that the effect of galantamine on cognitive function in this study corresponded well with that reported in a nursing home study the investigated the use of the drug donepezil for severe AD.2

References

  1. Burns A, Bernabei R, Bullock R, Jentoft AJ, Frölich L, Hock C, Raivio M, Triau E, Vandewoude M, Wimo A, Came E, Van Baelen B, Hammond GL, van Oene JC, Schwalen S. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol 2009 Jan;8(1):39-47.
  2. Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo controlled study. Lancet 2006;367:1057–65.

Thus, we now have reconfirmation that galantamine can protect the neurons of spatial memory in the brains of gerbils after transient global cerebral ischemia (when the entire brain temporarily is deprived of blood) following a stroke. Cerebrovascular disease is frequently a cause of dementia, and accordingly contributes to cognitive loss in Alzheimer’s disease (AD). Galantamine, used in the treatment of AD, has been shown to lessen the development of vascular dementia, resulting in enhanced cognition, and improved behavioral and daily living activities.

The Importance of a Well-Tuned Cholinergic System

The scientific literature has shown that galantamine helps to preserve and protect memory and other aspects of cognition by facilitating our cholinergic function—those aspects of brain activity that depend on the neurotransmitter acetylcholine (ACh). ACh is essential for concentration and focus, along with other crucial aspects of proper memory function. When the cholinergic system deteriorates, through either inadequate amounts of ACh or reduced responsiveness of neurons to ACh, dementia starts to make its presence known. In fact, a run-down cholinergic system is the neurophysiological hallmark of Alzheimer’s disease, not to mention other neurodegenerative diseases. The long-term consequence of cholinergic degradation is the wholesale death of neurons which ultimately leads to the grave.

Technically, galantamine acts as an acetylcholinesterase inhibitor that also shows allosteric (affecting both shape and activity) potentiation of nicotinic receptors. Acetylcholinesterase is the enzyme whose function is to destroy excess acetylcholine molecules in the neural synapses; when it is inhibited there is more acetylcholine. It can’t be emphasized enough that a well-functioning cholinergic system is critical for preserving and protecting memory and other aspects of cognitive function.


Galantamine was able to protect
neurons and memory following brain
injury, improving impaired spatial
memory in gerbils, even when given 3
hours after a simulated stroke.


In its second principal role, galantamine goes beyond other acetylcholinesterase inhibitors in that it has an effect on nicotinic receptors. This may be its most potent mode of action, one that is not shared by the other agents. It potentiates a class of receptor molecules that gather in the nerve impulses transmitted by ACh and act as tiny molecular attractors for ACh molecules. Called nicotinic acetylcholine receptors because they are very sensitive to nicotine as well as to ACh, they play an extremely important role for proper brain activity, without which the survival of memory would be in question. When cholinergic function declines as Alzheimer’s disease progresses, the nicotinic ACh receptors are reduced in number and sensitivity. Galantamine interacts molecularly with these receptors to help protect them from deterioration, thereby enhancing cholinergic function while protecting the neurons from cell death. Galantamine is a neuroprotector in this regard.

Less well known is its ability to potentiate the NMDA (for N-methyl-D-aspartate) receptors. Here galantamine plays a vital role in memory formation and the consolidation of short-term memory into long-term memory. Galantamine also facilitates synaptic transmission and has been found to have neuroprotective effects after global cerebral ischemia (when the entire brain temporarily is deprived of blood) as the Spanish studies attest.

Comparing Galantamine and Memantine

Back to the current paper, the researchers’ interest in the co-administration of galantamine and the drug memantine stemmed from the observation that conditions have been reported to worsen when galantamine is withdrawn. Memantine has been considered the drug of choice for late state Alzheimer’s (see the sidebar above). Although an earlier study had looked at the neuroprotective effects of galantamine and memantine in hippocampal slices subjected to oxygen and glucose deprivation, and demonstrated that both agents were neuroprotective, it was also found that memantine exerted less neuroprotection than galantamine.2 In the prior paper by the current authors, it’s worth repeating, neuroprotection against transient global cerebral ischemia was found for galantamine.3


Galantamine plays a vital role in
memory formation and the
consolidation of short-term memory
into long-term memory.


In the current study, the researchers tested whether galantamine or memantine, separately or together, protect hippocampal neurons from ischemia in vivo in a transient global cerebral ischemia model. This showed that memantine did not exert a clear neuroprotective effect and that spatial memory was lost. Nevertheless, galantamine and memantine together exerted neuroprotection and preserved spatial memory. However, the effects were no greater than the use of galantamine alone, indicating that memantine doesn’t interfere with the neuroprotective and behavioral effects of galantamine, but neither does it add anything in this important regard. Because both drugs are being used in clinical practice, and clinical trials are being performed with the association of both drugs, this evidence is arresting.

Galantamine is believed to exert neuroprotection mainly by inhibiting apoptosis. The neuroprotective effects of memantine are mixed. In some studies it does, and in others it doesn’t. Given that the target of memantine is the NMDA receptor, the mechanism by which it works is not clear.


Galantamine 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.


In conclusion, this study shows that galantamine prevented neuronal death and improved spatial memory that was impaired after transient global cerebral ischemia. Therefore, it could benefit patients suffering vascular dementia or stroke. This supports the view that clinical trials could be conducted to prove the therapeutic potential of post-ischemic administration of galantamine to patients suffering stroke.

This Button Is for You

Galanthus nivalis—
Moly
With a tip of the hat to Benjamin Button again, imagine for a moment (at least) that you could start over again from where you are right now, upgrading yourself with the quickest mind and fullest memory that life can offer. Forget that it’s not possible . . . at least not yet. Maybe it never will be (but don’t talk to any singularitarians!). However, consider that science is learning more all the time about how the mind works, and how best to tend to it, to preserve it, to protect it, and even to restore or enhance its extraordinary qualities. More evidence is compiling every day, and a growing number of neuroscientists think that all of the mind’s problems are ultimately solvable.

What we have learned about galantamine, how it works and what it can do for dementia and its possible prevention is enticing and ultimately reflective of what is in store. Bear in mind that this article is not merely about galantamine; it’s about neuroprotection, neuroenhancement, and all the possibilities for improvements of memory and mind to which we are the rightful heirs.

References

  1. Lorrio S, Negredo P, Roda JM, García AG, López MG. Effects of memantine and galantamine given separately or in association, on memory and hippocampal neuronal loss after transient global cerebral ischemia in gerbils. Brain Res 2008 Dec 10. [Epub ahead of print]
  2. 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 Jul 22;365(2):132-6.
  3. 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 Aug;322(2):591-9.


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

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