Galantamine Aids Recovery from Brain Damage

Galantamine Is Good for Humans Too

Galantamine Aids Recovery
from Brain Damage

In rats, it helps reverse cognitive impairment
caused by brain lesions that mimic Alzheimer’s
By Will Block

e glad you’re not a lab rat. Although their lives are pretty cushy most of the time—clean cages in climate-controlled rooms, plenty of food, other rats for company (and sometimes for sex), and no cats to worry about—scientists occasionally put them through a wringer in an effort to advance our knowledge of … whatever. How would you like it, for example, if some giant creature were to strap you down and inject something into your brain so as to cause brain damage?

That is what a team of researchers from the Netherlands, Sweden, Austria, and Hungary did recently, in an effort to establish an animal model of brain damage that other researchers could use in studies assessing the therapeutic effects of anti-Alzheimer’s agents.1 That being the objective, the brain damage would have to be of a kind that is characteristic of Alzheimer’s disease. And since the symptoms of that disease are caused primarily by deficiencies in the brain’s cholinergic system, … well, you figure it out.

Acetylcholine Deficits Lead to Alzheimer’s Disease

Oh, you’re not a neurologist? Sorry about that. Well, then, here’s a rundown. One of the most important neurotransmitters in the body (your body or a rat’s body or any body) is acetylcholine because of its wide-ranging domain of action, which includes the skeletal muscles, the smooth muscles of many organs, the exocrine glands, and various parts of the brain. This domain is called the cholinergic system, and it’s the brain part of the system (the central cholinergic system) that’s of interest here.

A decline in the brain’s acetylcholine (ACh) levels, or in the ability of ACh to function effectively in the brain, leads to the familiar symptoms of Alzheimer’s, beginning with significant memory impairment and progressing to a steady decline in other cognitive functions, the onset of behavioral disturbances, a loss of the ability to function in the activities of daily living, etc. It doesn’t take a neurologist to know how that story ends.

Plaques and Tangles Cause Severe Brain Damage

Other brain abnormalities associated with Alzheimer’s disease—notably the formation of harmful deposits called senile plaques and neurofibrillary tangles—are particularly dangerous because they destroy cholinergic neurons. That level of damage, however, is not what the European researchers wanted in their hapless rats. Their intent was to impair central cholinergic function in a manner that would simulate the earlier stages of the disease, when there are more and better options for treatment—options that might slow down, temporarily halt, or even temporarily reverse its course (there is no cure).

Indeed, medical scientists have been able to temporarily reverse the course of Alzheimer’s in patients who are in the mild to moderate stages of the disease. The agent with the best record in this regard is the plant-derived alkaloid galantamine, a memory-enhancing nutritional supplement that is also sold as a prescription drug called Reminyl®.*


*How can a supplement be a drug? It’s a matter of timing and law. Because galantamine had long been used as a supplement (probably for thousands of years) before it was licensed as a drug in 2001, it is indisputably still a supplement—legally and as a practical matter of fact. (For the history of galantamine’s use over the millennia, see “If Only Galantamine Could Talk …” in the August 2004 issue.)


Galantamine Boosts Acetylcholine Function

Galantamine acts on the central cholinergic system by increasing both the amount and the effectiveness of the acetylcholine that is available for use as a neurotransmitter. The “amount” trick is accomplished by inhibiting the action of acetylcholinesterase, the enzyme that breaks ACh molecules down. Galantamine’s action thus effectively boosts ACh levels in the brain; this is the basis for most anti-Alzheimer’s therapy in use today.

The “effectiveness” trick is accomplished by modulating the properties of one of the two main kinds of ACh receptors in the brain, called nicotinic receptors. Galantamine’s action tends to preserve and protect these receptors from deterioration and loss of function, which are characteristic features of cholinergic decline in Alzheimer’s disease.2 The enhanced effectiveness of the nicotinic receptors (compared with the deterioration that would otherwise occur) is an invaluable benefit provided by galantamine but not by the other anti-Alzheimer’s agents on the market. (For more on this important feature, see “Galantamine Helps Protect Your Neurons” in the April 2005 issue.)

How to Damage Rats’ Brains . . .

Now let’s get back to those rats (it’s not clear, by the way, whether they were Dutch, Swedish, Austrian, or Hungarian, but their squeaks sound about the same in any language, so it probably doesn’t matter). The researchers anesthetized the rats and placed their heads in a stereotaxic frame. This is a device that immobilizes the head and allows the insertion of a needle or other probe, such as an electrode, into the brain with a high degree of accuracy in terms of the point of entry, angle of entry, and depth of penetration. With a detailed knowledge of the anatomy of the rat brain, including the 3-dimensional coordinates of every structure, the researchers can bring the needle tip accurately to any target, even a small one that’s deeply hidden. (Similar devices are used in brain and spinal surgery on humans.)

In this case, the target was the medial septum, a thin, sheetlike structure in the basal forebrain. It’s connected to the hypothalamus, which controls many important body functions, and to the hippocampus, the brain structure primarily responsible for memory and learning. Bundles of cholinergic neurons from the medial septum project, via a structure called the fornix, to the hippocampus.

Previous research had shown that severing the fornix in rats’ brains seriously disrupts their memory and learning abilities, presumably owing to the irreversible shutoff of this source of ACh molecules. Other studies had shown, however, that the symptoms of cholinergic deficit can be induced by substantial but incomplete—and perhaps reversible—injury to the medial septum–fornix–hippocampus pathway. The authors of the present study chose this approach for their investigation of galantamine’s ability to counteract cholinergic damage.

. . . So They’ll Have Memory and Learning Problems

The researchers injected tiny amounts of an amino acid, NMDA (N-methyl-D-aspartate), into the medial septa of young adult male rats. NMDA is excitotoxic, i.e., it has the property of overexciting and poisoning cells or tissues by binding to NMDA-sensitive receptors on the cell membranes. The idea here was to damage but not destroy the medial septum, so that its cholinergic activity in the hippocampus would be impaired but not eliminated.

The procedure produced significant memory and learning deficits in the rats, as measured by their performance in a Morris water maze. In this test, they must find—and remember how to find again—an invisible, slightly submerged platform in a small tank of water so they can climb aboard and rest from their swimming. The success of their efforts is measured by the time it takes them to locate the platform on subsequent sessions in the tank. (This technique was described, from a rat’s point of view, in the article “CDP-Choline Helps with Memory” in the March 2005 issue.)

Remember This!

Memory is a chancy thing at best. Just ask a trial lawyer—cases are often won or lost on the recollections of witnesses, and no two witnesses will remember the same event exactly the same way. So why is memory so fallible, even in young people whose brains are still in the pink? The answer is … uh … oh, yes, the answer is that the process by which memories form in our brains is complex and subtle, and it’s not an all-or-nothing event, like switching a light on or off. It’s more like a light governed by a dimmer switch—the brightness will vary depending on how much juice it gets.

In your brain, the primary memory “juice” is the neurotransmitter acetylcholine (ACh), and the circuitry is electrochemical, not electric. Nerve impulses from the medial septum and other cholinergic sources (most prominently a structure in the basal forebrain called the nucleus basalis of Meynert) travel via the fornix to the hippocampus, whose main functions are the regulation of memory and learning. At the synaptic junctions there, ACh molecules are released and, depending on various factors, either excite or inhibit the activation of hippocampal neurons. In the former case, a nervous impulse is propagated further; in the latter case, it is not. Both events are important in memory formation.

The process of forming a short-term memory (such as remembering an unfamiliar phone number long enough to dial it) begins when incoming nerve impulses representing a certain idea launch a cascade of intracellular chemical reactions in hippocampal neurons. This results in the activation of certain existing neuronal proteins, which stimulate the production of more neurotransmitters of various kinds for the transmission of more nerve impulses across existing synapses. The net effect is to establish a localized neuronal network based on the original nerve impulses. The new network, in effect, becomes the memory.*


*The human brain contains about 100 billion neurons, each with an average of about 10,000 synaptic connections with other neurons. Thus there are about 1 quadrillion synaptic connections, and the number of possible neural pathways among all these connections is incomparably larger than the number of elementary particles in the known universe.


But—easy come, easy go. Unless the strength of the network’s neuronal connections is reinforced by frequent infusions of “juice” (i.e., by your concentrating on the item and repeating it in your mind, thereby sending more ACh-mediated signals to the hippocampus), the memory will quickly fade, like the light from a dimmer switch, as the neurons involved become parts of new connections in new networks (new short-term memories crowding out the old).

If you do concentrate and repeat often, however, you are laying the groundwork for long-term memory (such as remembering your own phone number). Also, of course, events are constantly occurring that imprint themselves more or less strongly on your memory because of their intrinsic interest or uniqueness, especially if they’re linked to a strong emotion—experiencing a tornado, e.g., or encountering an honest politician.

Here the process entails a more complex chain of chemical reactions, in which the existing proteins mentioned earlier stimulate the activation of genes that will cause the synthesis of new proteins of different kinds. The new proteins are responsible for creating new neural synapses that are, in effect, dedicated to the memory in question, at least until it can be transferred to other regions of the brain for permanent storage. That process is even more complex, and we have only the dimmest understanding of how it occurs.

Now, do you remember everything you’ve learned from this article? What? How come? You just read it, didn’t you?

Galantamine Treatment Improved the Rats’ Performance

Beginning 1 hour after the surgery and continuing twice daily for 7 days, the researchers administered galantamine by intraperitoneal (in the abdominal cavity) injection in doses of either 1 or 3 mg per kg of body weight [this corresponds to 75 or 225 mg for a 75-kg (165-lb) person]. The control rats, whose medial septa had been injected with saline solution instead of NMDA so they would undergo the same kind of surgical trauma as the experimental rats, were now injected with either saline solution or galantamine.

As expected, the control rats performed normally in the water maze, and treatment with galantamine had no effect on them. By contrast, the cholinergically impaired rats had serious memory and learning deficits. Treatment with galantamine, however, greatly improved their performance, producing significantly shorter total swimming distances and shorter times to find the platform in the initial phase of the protocol. Similar results were obtained in the subsequent phase, when the platform’s location had been changed so as to confuse the rats. Overall, the best results were obtained with the lower dose of galantamine, although there was no clear dose-response relationship.

Later, when the rats’ brains were dissected and analyzed, the researchers found that NMDA had produced visible shrinkage of the cholinergic neurons, but (as desired) without extensive loss of neurons. This situation thus mimicked, at least to some extent, the mild cholinergic deficit seen in the early stages of Alzheimer’s disease, rather than the massive deficit that characterizes the advanced stages, when neurons die in great numbers.

Galantamine Helps with Alzheimer’s and MCI

Galantamine’s beneficial effects on memory and learning abilities in the mildly brain-damaged rats thus suggest that it is able, to some degree, to counteract the consequences of neurodegenerative processes. Whether this ability is derived mainly from galantamine’s action as an acetylcholinesterase inhibitor or as a modulator of nicotinic acetylcholine receptors is not known.

In any case, the results are in accord with multiple studies in humans demonstrating galantamine’s ability not just to slow or temporarily halt the progress of Alzheimer’s disease in mild to moderate cases, but also to temporarily reverse it for up to one year before the decline begins anew. This buys the patient the most precious commodity there is: time. (See “Galantamine Offers Sustained Cognitive Benefits” in the December 2004 issue and the sidebar “Galantamine Buys Time” in “Green Tea May Help Prevent Alzheimer’s” in the January 2005 issue.)

It’s important to note that galantamine has also been shown to be beneficial for a common precursor condition—and major risk factor—for Alzheimer’s disease, namely, mild cognitive impairment (MCI). This recent discovery provides confirmation of our long-standing belief that, if galantamine can successfully treat Alzheimer’s disease (as indeed it can), it should also be successful in treating, and perhaps helping to prevent, MCI. (The research in question was discussed in “Galantamine Improves Memory in MCI” in the February 2005 issue.)

Take Care of Your Brain

You may not be a rat (OK, you’re definitely not a rat), but brain damage of the Alzheimer’s type is, alas, a possibility in your future, because you’re alive and growing older. Prudence suggests that you do everything you can to forestall such a fate. So remember to take good care of your brain. One way to do that is with galantamine.

References

  1. Mulder J, Harkany T, Czollner K, Cremers TIFH, Keijser JN, Nyakas C, Luiten PGM. Galantamine-induced behavioral recovery after sublethal excitotoxic lesions to the rat medial septum. Behav Brain Res 2005;online preprint:PMID 15951032.
  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.

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.

It’s also a good idea to take the following:

  • Green tea polyphenols, a class of antioxidants, operating together as a system, that can also fight amyloid-beta toxicity
  • Vitamin C and Vitamin E, which have been shown to work together to help protect your brain's hotbeds of free radical activity
  • Turmeric curcuminoids, a system of antioxidants that helps protect your neurons from damage or death caused by amyloid-beta
  • Folic acid, vitamin B6, and vitamin B12, important vitamins that help prevent damage to mitochondria (where they help repair DNA damage), cofactor the production of nitric oxide, and reduce levels of homocysteine (a neurotoxin)
  • Lithium, an important brain food that is found in the bottled waters of American and European health spas ... that also lowers the toxicity of amyloid-beta while causing an increase in neurotrophic factors that help induce neurons to repair themselves when under stress ... that helps cause an increase in gray matter and helps enhance neurogenesis of hippocampal neurons


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

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