Galantamine’s Role May Be Expanding
These anti-Alzheimer’s agents ought to oppose each other, but
preclinical evidence suggests the opposite
One of the hallmarks of a great chef is the almost mystical ability to know what ingredients will work well together—even when they seem terribly mismatched—in the creation of a new dish. Nowhere is this talent more evident than on the cable TV show Iron Chef America, where two renowned chefs battle to outdo each other in the creation of five (each) culinary masterpieces, all in exactly one hour, for judging by a panel of three discriminating food critics. The dishes are judged on taste, naturally, but also on the artistry of their plating and on “originality in the use of today’s secret ingredient.”
The chefs’ originality and virtuosity are dazzling, and the competitions are exciting to watch (would that there were some kind of “smell-a-vision”!). If there were a Nobel Prize for creating fabulous dishes, impromptu, using ingredients and techniques of mind-boggling variety, these chefs would be visiting Stockholm pretty often.
Nobel Dream, Noble Cause
Back in the real world, other people seek new creations, but at a slower pace and with much less flair. Still, they too can dream of a Nobel Prize, because they’re scientists, and that’s what scientists do. When medical scientists aren’t dreaming about the prize in Medicine or Physiology, they’re trying to discover something that might get them that ticket to Stockholm, or that will at least get some journal editor to accept their next manuscript for publication.
Recently, the editor of the Journal of Clinical Pharmacology accepted two papers by researchers in the Division of Geriatric Psychiatry at the University of St. Louis, discussing the rationale for a new “recipe” for treating Alzheimer’s disease (AD).1,2Although it would probably not taste good, it might do good for the victims of this terrible disease—and that’s the whole idea.
Galantamine and Memantine—Different Modes of Action
Two things are of particular interest regarding this recipe (which did not originate with the St. Louis authors):
The other drug is a real drug, the newest of the anti-Alzheimer’s medications on the U.S. market. It’s a synthetic compound called memantine, which is sold under the brand names Axura® and Namenda®. Memantine acts very differently from galantamine. Whereas galantamine acts to enhance cholinergic function (neural activities that depend on acetylcholine as the neurotransmitter), memantine acts to inhibit glutamatergic function (neural activities that depend on glutamate as the neurotransmitter). Both of these neurotransmitters are vital to information processing and cognitive function; they play key roles in memory and learning, which could not occur without them.
Glutamate, the most widely distributed neurotransmitter in our brains, is the anion (negative ion) of glutamic acid, a common amino acid found in our food.* With respect to cognitive function, glutamate acts primarily through neuronal receptors called NMDA receptors (for N-methyl-D-aspartate), which play a crucial role in memory formation and the consolidation of short-term memory into long-term memory. Glutamate-related imbalances in NMDA receptor function are implicated in the pathology of Alzheimer’s and other neurodegenerative diseases.
*Glutamate is primarily responsible for the umami taste, one of the five basic taste sensations (the other four being sweet, sour, salty, and bitter).
Two Hypotheses, One Throne
For decades, it was thought that the progressive deterioration in cognitive function seen in Alzheimer’s patients was primarily, if not exclusively, the result of cholinergic dysfunction—reduced levels and activity of acetylcholine in the brain, especially in regions such as the hippocampus and cerebral cortex. This was called the cholinergic hypothesis of Alzheimer’s disease. Its influence drove the development of the major anti-Alzheimer’s agents (donepezil, rivastigmine, and galantamine), all of which have cholinergic activity, i.e., they tend to increase acetylcholine levels or activity (both, in the case of galantamine). The FDA has approved these agents for use in cases of mild to moderate AD.†
†Analyses of data obtained in previously published clinical trials of galantamine in the treatment of mild to moderate Alzheimer’s have shown that galantamine is also safe and effective in cases that can be described as “advanced moderate” (i.e., just shy of severe).
Although the cholinergic hypothesis has not been dethroned, it has been forced to share the throne with the glutamatergic hypothesis, which holds that glutamate-related excitotoxicity involving NMDA receptors leads to neurodegeneration and cell death in AD. Excitotoxicity, a curious-sounding term, refers to the harmful effects of overactivity of a neurotransmitter, which can overly excite (in an electrochemical sense) the neurons, resulting in neuronal damage or death. It’s a classic case of too much of a good thing being a bad thing.
The most notoriously excitotoxic neurotransmitter is glutamate. Achieving desirable levels of glutamate activity without incurring its excitotoxic effects is an important goal in Alzheimer’s therapy—hence the development of memantine, which has antiglutamatergic activity, i.e., it tends to inhibit the activity of glutamate at NMDA receptors. The FDA has approved memantine for use in cases of moderate to severe AD. (Like galantamine, by the way, memantine has been shown to protect against neurotoxicity caused by amyloid-beta, the principal protein component of the plaques that foul the brains of Alzheimer’s victims.)
Opposites Cooperate for Net Positive Effect
The strategies outlined above sound good, because with galantamine and memantine each acting beneficially in its separate “ergic” arena, the two should complement each other and provide all the more benefit to patients who take them simultaneously, right? Right—probably, although this has yet to be demonstrated in clinical trials. But here’s the rub: the two arenas are not separate—they overlap, especially with regard to NMDA receptors. Whereas memantine reduces glutamatergic activity, galantamine increases it.
Uh-oh! Here are the opposing mechanisms of action we mentioned earlier. They should throw a monkey wrench into the works—but apparently they don’t! Detailed considerations of the biochemical mechanisms involved, which are too complex to go into here (you would need to take a course in neurophysiology first), have led the authors to conclude that the effects of both agents, working together, should have net positive effects on both the cholinergic and glutamatergic systems in the brains of Alzheimer’s patients.1 This conclusion is not just theoretical but is supported by evidence obtained from preclinical studies (laboratory and animal) on the mechanisms of action of the two agents.2
All of which illustrates that Alzheimer’s disease is even more complicated and mysterious than had long been thought. We now know that most neurons in the brain have receptors for not just one type of neurotransmitter, but several or many. That means that all such neurons are part of multiple “ergic” systems and can respond in exceedingly complex and variable ways—including opposite ways, depending on the circumstances. In Alzheimer’s, the two primary systems are believed to be the cholinergic and glutamatergic, but the disease also involves dysfunctions in the dopaminergic, noradrenergic, and serotonergic systems (which utilize dopamine, noradrenaline, and serotonin, respectively, as neurotransmitters), and perhaps others as well.
Improving Neural Signals Helps Cognition
A fascinating speculation regarding the interaction between galantamine and memantine has to do with the signal-to-noise ratio in neural transmissions. Like radio or television signals, which are subject to a certain amount of unwanted “noise” caused by spurious electromagnetic effects, transmission of nerve impulses in our brains can be degraded by noise caused by spurious electrochemical effects. Such noise may be particularly “loud” (pervasive) in Alzheimer’s disease and may therefore be partly responsible for the deterioration in cognitive function.
“Galantamine has been shown to be
effective for treatment of AD, and its
unique dual mechanism of action
makes it an optimal drug for exploring
new combination treatments . . .”
Computer simulations of the biochemical interactions between galantamine and memantine in the human body predict that combination therapy with these two agents may enhance the neural signal-to-noise ratio even more than memantine does by itself. This should improve the patients’ cognitive function, or at least retard its decay.
Galantamine Is Optimal for Combination Therapy
In summarizing their studies, the authors stated, in one of the papers,1Galantamine has been shown to be effective for treatment of AD, and its unique dual mechanism of action makes it an optimal drug for exploring new combination treatments with other drugs that modulate neurotransmission, such as memantine. Although these two drugs appear to have opposing mechanisms of action, a physiological analysis of their activities provides a rationale for why they may work well together to improve cognition.And in the second paper, they stated,2Galantamine may work synergistically with memantine through independent pathways to enhance synaptic activity. … Combination therapy … has the potential to provide additive or synergistic benefits that either drug alone cannot achieve.
It’s all still conjecture at this point, like a new recipe that hasn’t yet been put to the taste test, but it suggests strongly that galantamine’s expanding role in the realm of Alzheimer’s disease may soon warrant another star in its rating. Stay tuned.
Dire Warning on Dementia
With the great advances in medical science and technology during the past century has come a steady, dramatic increase in average human lifespan, and it shows no sign of letting up. This boon to mankind has come with a huge price tag, however: the rapidly increasing rate of dementia in the elderly, aided and abetted by the epidemic rise of type 2 diabetes. What good is it to live longer if you lose your mind along the way?
Life enhancement is all about living longer and living well, which means that one must act aggressively to prevent the degenerative changes of aging that seem to be—but are not necessarily—inevitable. Prevention, not treatment, is the key. If the prevention of dementia is not undertaken on a large scale, the number of people suffering from dementia worldwide is expected to nearly double every 20 years, according to scientists from Alzheimer’s Disease International, an umbrella organization of Alzheimer’s associations around the world.1
Currently, 24.3 million people are believed to suffer from dementia worldwide. That number is expected to reach 42 million in 2025 and 81 million in 2040 unless something is done about this epidemic. The rate of increase is expected to be three to four times higher in the developing regions of the world than in the developed regions, and the bulk of the increase will occur in India, China, south Asia, and the western Pacific.
The public health implications of this epidemic are dire, and it’s not clear how various countries will be able to absorb the enormous costs involved. As taxpayers, we will all be hit hard. As individual consumers of health care, though, we can all do our best to avoid the terrible fate that awaits so many others.