Fire Up Your Brain with Galantamine

We’ll get to that matter of broken insulation. First, however, let’s consider a provocative idea put forth recently by Dr. George Bartzokis, a neurologist at UCLA’s David Geffen School of Medicine, who stepped outside the box to have a fresh look at something important to all of us: our brain function and how it deteriorates with age.¹ The box in question encompasses our thinking about the use of acetylcholinesterase inhibitors (AChEIs) for the treatment of neurodegenerative diseases, particularly Alzheimer’s disease, the greatest scourge of them all.

Bartzokis believes that the indisputable benefits of AChEIs may be due in large measure to something other than what we’ve thought all along. To put his view into perspective, let’s have a quick look inside the box he broke out of. It’s not that there’s anything wrong in there—there certainly isn’t, as he’s quick to point out—but rather that the box is too small to encompass the larger picture he sees.

Cholinergic Function—Key to Cognition

Our learning, memory, and other cognitive functions depend critically on the actions of the neurotransmitter acetylcholine (ACh), which facilitates the propagation of neural signals (nerve impulses) across the synapses (gaps) between neurons in certain regions of the brain. Brain activity that depends on ACh as the neurotransmitter is called cholinergic function. In Alzheimer’s disease, ACh levels decline markedly, degrading cholinergic function and, therefore, our cognitive functions, especially memory.

ACh levels are regulated in part by the enzyme acetylcholinesterase (AChE), which destroys excess ACh molecules as part of a necessary biochemical balancing act to maintain proper cholinergic function. As ACh levels decline sharply in Alzheimer’s disease, however, it becomes desirable to inhibit the action of this enzyme so as to maintain healthy ACh levels and, therefore, normal cognitive function, for as long as possible. That’s what acetylcholinesterase inhibitors do.

Galantamine—Potent and Versatile

It has long been known that AChEIs, such as the plant alkaloid galantamine, are effective in alleviating the symptoms of Alzheimer’s disease (AD) and slowing its inevitable course, usually for a period of about 6 months to a year, before the decline resumes in earnest. (There is still no cure for AD, which is ultimately fatal.) Some AChEIs, such as donepezil and rivastigmine, are prescription drugs. Galantamine too is sold by prescription, but, unlike the others, it’s also available as a nutritional supplement, owing to its use as such for many years before the FDA approved it as a “drug” in 2001.

In addition to being an acetylcholinesterase inhibitor, galantamine has another mode of action that the other AChEIs do not. Galantamine is a potent allosteric modulator of nicotinic acetylcholine receptors, a fancy way of saying that it improves the receptivity of neurons to acetylcholine molecules that are trying to transmit a nerve impulse across a synaptic junction.

In other words, galantamine not only enhances the availability of ACh molecules (as do the other AChEIs), but it also makes them more effective in accomplishing their appointed task. Abundant evidence suggests that galantamine’s exceptional efficacy as a treatment for mild to moderate Alzheimer’s disease rests mainly on its protection and stimulation of nicotinic acetylcholine receptors.

Much additional research has indicated that galantamine is also effective, to varying degrees, against other dementias, such as Lewy body dementia, vascular dementia, and the dementia of Parkinson’s disease. It has even shown some benefit against schizophrenia, which is not a dementia.*

*For information on galantamine’s therapeutic versatility, see “Galantamine Helps in Parkinson’s Disease with Dementia” (December 2003), “Galantamine Suppresses Brain-Cell Suicide” (February 2004), “Galantamine’s Antidementia Action Expands—Sort Of” (March 2004), “Galantamine May Help You Remain a Smart Cookie” (April 2004), “Galantamine May Help in Schizophrenia” (October 2004), “Galantamine Offers Sustained Cognitive Benefits” (December 2004), “Galantamine Improves Memory in MCI” (February 2005), “Galantamine Helps Protect Your Neurons” (April 2005), “Galantamine Can Modify Alzheimer’s Disease” (October 2005), “A New Window on Galantamine’s Benefits” (November 2006), and “Galantamine Benefits Both Alzheimer’s Disease and Vascular Dementia” (January 2008).

A Startling Idea from Outside the Box

Because AChEIs are effective in treating the symptoms of AD even while the degenerative process continues seemingly unabated, it has become easy to assume that that’s all they do. Enter Dr. Bartzokis—or rather, exit Dr. Bartzokis from that particular conceptual box, to do some original thinking. He has suggested that: (1) there may be a neurophysiological dimension to Alzheimer’s disease that has not been adequately explored, and (2) the beneficial effects of AChEIs may be attributable in part to their operation in this hitherto underappreciated domain.*

*In his paper, Bartzokis makes no mention of galantamine or any other AChEI; all references are to AChEIs generically.

The premise of his theory is that improving cholinergic function at neuronal synapses is not the sole mode of action of AChEIs, as has generally been assumed. In particular, the premise is that such neuronal synaptic effects may not even be the principal mode of action underlying the disease-modifying or -delaying effects of the AChEIs—a startling idea from the viewpoint of conventional wisdom (the box) in this arena.

Bartzokis proposes that improving cholinergic function can, in addition to enhancing synaptic neurotransmission, have beneficial nonsynaptic effects, by improving certain of the brain’s lifelong developmental processes. His focus is on those processes that involve myelin, the white, fatty material that acts as an electrical insulator—the myelin sheath—on most of the brain’s neuronal axons. (The brain’s white matter is white because of myelin.) If you’re not familiar with the structure and function of neurons, now would be a good time to bone up (brain up?) on this subject by reading the sidebar “Of Axons, Myelin, and Really Big Numbers.”

The Myelin Model of the Human Brain

In his paper, Bartzokis outlines what he calls the myelin model of the human brain, which he has been developing over the last several years (in numerous published papers). It involves the fact that the myelination of axons in the human brain is not fully developed at birth, but develops gradually throughout the first four decades of life, peaking at around age 45; thereafter, the brain’s myelin content declines gradually for the rest of our lives, as the myelin sheaths degrade. From the myelin perspective, these two broad phases in the life of the brain—a development phase (myelination) and a degeneration phase (demyelination) represent a curved trajectory, as seen below.

The approximate myelination trajectory of the frontal lobe of normal human brains (there are large individual variations). Adapted from Ref. 1.

The presence of an intact myelin sheath, with its nodes of Ranvier (see the sidebar), boosts not only the speed of nerve impulses (10-fold) but also their frequency (34-fold) over those of unmyelinated axons. Thus, in Bartzokis’s analysis, maximal myelination can produce up to a 340-fold increase in effective bandwidth for information transfer along neural pathways in the human brain, an organ that is unique even among primates in the extensive and pervasive myelination of its axons (most animals have little or no myelination).* He believes that our brains’ huge capacity for information processing depends in large measure on myelination. He states (literature citations omitted),¹

*Although we speak of “dumb” animals, recent research has provided new evidence of how much smarter they are than we ever realized. For a fascinating look at this subject, see the cover story, “Inside Animal Minds,” in National Geographic, March 2008.

From the perspective of this model, the development and maintenance/repair of myelin’s functional integrity over our lifespan is the single most critical element for acquiring and maintaining normal human cognition and behavior. In short, myelin represents the “Achilles’ heel” of brain development as well as degeneration. . . .

In adulthood, healthy individuals who myelinated normally go on to lose up to 45% of their myelinated fiber length in the degenerative phase of their myelination trajectory. The degenerative process of myelin breakdown recapitulates the myelination process in reverse, with the most vulnerable later-myelinated regions and functions succumbing first. This age-related myelin breakdown underlies the . . . [pattern of] . . . cellular changes that define the highly prevalent age-related degenerative dementing diseases, such as AD.

He goes on to say that in cases of dementia, demyelination begins early in the disease process, before a diagnosis of dementia or even its common precursor, mild cognitive impairment (MCI), can be made. It can be detected in living humans even before the fifth decade.

Where’s the Evidence? (Patience . . .)

So much for the myelin model of the human brain, which is certainly intriguing. But where’s the evidence that improving cholinergic function with acetylcholinesterase inhibitors, such as galantamine, can have the kind of nonsynaptic effects associated with the myelination trajectory that underlies this model?

There is no direct evidence yet, but it could be forthcoming soon because, Bartzokis points out, noninvasive brain-imaging technologies now make it possible to assess the trajectory of myelin development and its subsequent degradation in the brains of living humans, as well as to observe certain physical changes in the brain associated with changes in cholinergic function.

AChEIs Benefit Brain Disorders in Young and Old

OK, but what are the reasons for believing that such evidence will be forthcoming? To that central question, Bartzokis devotes several pages of detailed analysis; we’ll summarize the highlights.

Dr. George Bartzokis

Furthermore, recent evidence suggests that the brain’s nicotinic acetylcholine receptors—cellular receptors that are activated by acetylcholine (and by nicotine; hence the name)—are found not just on neurons but also on other, nonneuronal cells, especially of a type called oligodendrocytes (which are one of the four types of glial cells). That’s significant because oligodendrocytes are the source of the brain’s myelin—these sheetlike glia wrap themselves around axons in multiple turns, and that is what constitutes each segment of the myelin sheath in the central nervous system. (In the peripheral nervous system, the myelin sheath comes from a different type of cell, called Schwann cells.)

AChEIs—Your Myelin Sheaths’ Friends

Thus, there appears to be a direct connection between cholinergic function—and therefore, presumably, the action of AChEIs, such as galantamine—and the myelin sheath. Supporting this idea is the fact that in healthy older individuals, there are age-related declines in both myelin and nicotinic acetylcholine receptors, and both of these declines are exacerbated in multiple degenerative brain disorders.

It’s not unreasonable to suppose that maintaining healthy cholinergic function throughout life is important for maintaining, as much as possible, the integrity of axonal myelination in the brain. Indeed, AChEI treatments have demonstrated efficacy in both developmental and degenerative brain disorders, as noted above, and they have also demonstrated preventive effects, according to Bartzokis.

It’s noteworthy that AChEIs can improve cognitive function in patients with MCI and that such treatments delay the progression of MCI to AD. It’s hard to explain the benefits to MCI patients on the basis of synaptic cholinergic deficits, because cholinergic function tends to be normal or elevated in these patients (and even in early AD patients), according to the results of several postmortem studies from several research groups. To Bartzokis, these findings suggest that the short-term memory deficits seen in MCI are caused not by cholinergic deficits but by some other, nonsynaptic mechanism—probably myelin degradation.

Got Myelin?

So, how does your brain feel after reading all that? Well-myelinated, we hope. And if not, there’s always galantamine, which may help preserve and protect those precious myelin sheaths, “broken” as they may be by the nodes of Ranvier.

It’s frustrating to have to wait and see whether the kinds of evidence discussed above will, in fact, be forthcoming, but at least we have plenty of new food for thought— always a good thing. We don’t want to be like the people Bertrand Russell was talking about when he said, “Most people would die sooner than think; in fact, they do.”

Reference

1. Bartzokis G. Acetylcholinesterase inhibitors may improve myelin integrity. Biol Psychiatry 2007;62:294-301.