Galantamine Is Good for Mice and Men

ehold the lowly mouse. Let us forget, for the moment, that most people regard mice as vermin, to be dispatched as ruthlessly as possible, with nary a thought to the fact that they really are kind of cute and cuddly, as rodents go. And they have dynamite personalities too—at least Mickey did. And cats love them . . . .

But who really loves mice? Medical researchers, that’s who. To scientists trying to unravel the fantastically complex workings of the human body in both health and disease, there’s nothing better than a mouse—better yet, hundreds of them. Sure, there are also rats and guinea pigs and fruit flies and roundworms and monkeys and Japanese quail (see the article on page 28 of this issue), and even dogs and cats (dogs and cats?!), along with many other noble creatures, all of which have given their all for the sake of medical research, so that we humans could have longer, healthier, happier lives.

But for compact, easy-to-manage, fast-reproducing, metabolically well-suited organisms on which to test our ideas on how to improve the human condition, nothing beats your basic lab mouse. Without them—and all the other animals mentioned—we would still be in the Dark Ages of medicine, enduring immense amounts of human suffering as we (including our children) succumbed to myriad fatal diseases that are now but a distant memory.*

*Antivivisectionists increasingly clamor for animal research to be supplanted by computer simulations so as to spare our fellow creatures from a dismal life (and death) in some laboratory. Their hearts are in the right place, but the idea is extraordinarily naive—it betrays a lack of understanding of physiology or computers, or both.

Galantamine Resists Memory Impairment

Speaking of memory (uh, we were, weren’t we?) brings to mind the subject of dementia, and Alzheimer’s disease in particular. There are dozens of different forms of dementia, but Alzheimer’s is the most prevalent, followed by vascular dementia; all the rest are small potatoes by comparison. The hallmark symptom of Alzheimer’s is a progressive, irreversible memory loss that ultimately robs its victims of their very identity.

Just when this dreadful process begins is hard to say, because relatively benign forms of memory loss (which go by different names to reflect their different spectra of symptoms) are a nearly universal feature of aging. We’re all familiar with that kind of “old-folks” forgetfulness, and we take it in stride, because we’ve accepted the idea of its inevitability. And we don’t worry too much about it, because it’s harmless. Usually.

Uh-oh. When is it not harmless? You know the answer: when it’s a setup for Alzheimer’s or some other form of dementia. A prevalent form of memory impairment in otherwise healthy people is called mild cognitive impairment (MCI), which can be thought of as a transitional phase between normal aging and early (mild) dementia. There is no question that MCI is a major risk factor for dementia, so it’s worthwhile (to put it mildly) to try to prevent it or at least slow down its progression. The earlier one starts, the better.

Possibly the best approach to this objective is to use galantamine, a chemical compound isolated from various flowers, which has proven to be beneficial in the treatment of mild to moderate Alzheimer’s disease and which shows great promise—not surprisingly—in treating MCI as well. (See Galantamine May Help with Mild Cognitive Impairment in last month’s issue of Life Enhancement.)

Beta-Amyloid Is Bad Brain Matter

It would be great if there were a reliable method of determining when Alzheimer’s disease was imminent or had already begun. Although there is no such method yet, researchers are devising ever more sophisticated tests of memory and other aspects of cognitive function, such as learning ability. They are also making progress in methods of physical diagnosis through brain imaging, using techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). The idea, of course, is to detect brain abnormalities that are characteristic of Alzheimer’s disease.

One of the hallmark physical abnormalities of the disease is deposits of a waxy plaque called beta-amyloid in certain regions of the brain, notably the hippocampus, which is associated with memory and learning. Beta-amyloid consists primarily of protein; it comes from a precursor protein called . . . amyloid precursor protein (APP). The process is one result of neurodegeneration—the degeneration of nerve tissue. And what causes that? Many factors, probably. In a moment we’ll see what one probable factor is, based on some recently published research in neuroscience.

Transgenic Italian Mice Get Alzheimer’s

Which brings us back to mice (that introduction had to be leading somewhere). One of the great things about mice is that one can mess with their genes, so to speak, in order to give them certain characteristics that are useful in medical research. This is done using the techniques of genetic engineering. One such technique is to transfer a gene from one type of organism into the DNA of another, thus introducing a desired characteristic into the host organism (in this case, a mouse). A mouse with such a transplanted gene in its DNA is called transgenic. For example, one can bring in a gene responsible for the production of an antibody (a specialized type of protein) that will neutralize the action of a given protein normally found in the mouse’s cells.

A group of researchers in Italy has made interesting use of a type of transgenic mouse called AD11, in which an antibody produced by the “alien” gene neutralizes the mouse’s nerve growth factor (NGF), a protein that stimulates the growth of certain types of nerve cells.¹ Now comes that “probable factor” in neurodegeneration that we promised you a moment ago. Without NGF, the poor little mouse’s aging brain suffers a form of progressive neurodegeneration that resembles Alzheimer’s disease in many ways, both behavioral and neuroanatomical, including the loss of neurons in certain parts of the brain and the formation of beta-amyloid. (This jibes with the suggestion by some scientists that a decrease in NGF function in human brains may be a contributing factor in the onset of Alzheimer’s.)

Galantamine to the Rescue

So the AD11 mice get what appears to be experimentally induced Alzheimer’s disease, and that makes them very useful for study. The Italian researchers wanted to determine the extent to which the deficit in NGF function in these mice could be linked to the observed neurodegenerative symptoms, and, more importantly, to see whether these symptoms could be prevented or alleviated by treatment with NGF or . . . galantamine.

Whoa! Trying NGF as a treatment in NGF-impaired mice is obvious, but why galantamine? To be sure, we know that galantamine is an effective treatment (probably the best treatment) for Alzheimer’s, but what is its connection with NGF? Well, it turns out that NGF fosters the proper development of a certain class of neurons in the basal forebrain during growth and adulthood. These neurons are called cholinergic, because what makes them work, so to speak, is the neurotransmitter acetylcholine. And galantamine’s action in the brain is to boost the levels and activity of acetylcholine, via two different mechanisms that we’ll touch upon below.

Here’s a recap: in the basal forebrain, a deficit of nerve growth factor retards the development and proper function of cholinergic neurons, which depend on acetylcholine as their neurotransmitter. This process, which entails not only a loss of neuronal function but also a loss of many neurons themselves, is a form of neurodegeneration. The researchers wanted to know whether galantamine, a known anti-Alzheimer’s agent, would counteract this specific form of NGF-related neurodegeneration in this specific kind of NGF-impaired mouse. So they tried it—and it did (so did NGF, by the way). Galantamine significantly “rescued” (in medical jargon) the cholinergic deficit by preventing the loss of cholinergic neurons.

Galantamine Reduces Beta-Amyloid

The researchers also wanted to know whether galantamine would reduce the deposits of the beta-amyloid precursor APP, which we mentioned earlier. So they tried it—and it did, markedly (in this case, however, NGF had no effect, for unknown reasons). As the mice aged, their APP deposits gradually turned into beta-amyloid, and the researchers wanted to know whether galantamine would reduce those deposits as well. So they tried it when the mice were 6–6.5 months old—and it did, markedly (and so did NGF, this time). The beta-amyloid deposits were in the hippocampus.

The results of the Italian research add a few more small pieces to the huge puzzle that is Alzheimer’s disease. Many factors can be involved in the chains of events leading to the neurodegeneration that is so characteristic of the disease. The causal links among the various risk factors involved, and their individual roles in forging those chains of events, remain largely elusive, and no comprehensive theory that can account for all the clinical and neuropathological features of the disease has yet emerged.

Meanwhile, however, it’s good to have a few more bits of confirming evidence for the efficacy of galantamine in combating Alzheimer’s. (We’re assuming that the mouse results would be valid in humans as well; that’s usually a good assumption, but there’s no guarantee.)

Galantamine Modulates Nicotinic Receptors

A significant aspect of the Italian study was the discovery that galantamine’s mode of action was not the same as that of the drugs—called acetylcholinesterase inhibitors—that are widely used to treat Alzheimer’s disease in humans. Although galantamine is itself an effective acetylcholinesterase inhibitor and owes much of its efficacy to that fact, it has an additional mode of action that the drugs do not have: it is a modulator of nicotinic receptors in the brain. We need not go into the details of all this here—they have been covered at length in previous articles about galantamine in Life Enhancement.* Suffice it to say that this second mechanism gives galantamine a substantial advantage over the drugs in the Alzheimer’s arena.

*See, e.g., Galantamine Improves Both Alzheimer’s and Vascular Dementia and Remember Galantamine? (How Could You Forget?) in the July and September 2002 issues, respectively.

That advantage became dramatically evident when the researchers tried two of the Alzheimer’s drugs, tacrine and physostigmine, in the transgenic mice: they were ineffective. From this and other evidence, they concluded that galantamine must have acted in its own unique way, by modulating the nicotinic receptors in the mouse brains.

Act Early to Head Off Alzheimer’s

The Italian research underscored what had already become clear from numerous other studies on galantamine’s role as an anti-Alzheimer’s agent: its efficacy is greatest in the early stages of the disease, before the effects of the neurodegeneration have taken such a hold on brain function that they become irreversible.

The message here, of course, is that early, preventive action against the possibility of Alzheimer’s is a wise strategy—it’s easier to hold off a weak foe than a strong one. So remember not to forget to be wise. And the next time you encounter a mouse, be kind.

Reference

1. Capsoni S, Giannotta S, Cattaneo A. Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad Sci 2002 Sep 17;99(19):12432-7.

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