Every Body and Mind Needs Choline
What's Old with Acetylcholine is New to Us
Research Provides New Awareness of the Importance of this Ancient Molecule

By Will Block

ll the jokes about "snail mail" notwithstanding, the postal service is an amazingly efficient enterprise that handles mountains of letters and packages (and junk) with such reliability that we seldom give a thought as to whether or not our mail will be delivered. We assume that it will be, because it almost always is.

The logistics and infrastructure of mail delivery boggle the mind. Think of the myriad people and things and actions required for the transfer of just one letter from you to Cousin Charlie in another state. Think of the innumerable industries whose goods and services are required to make those things and actions possible. And think of the billions of pieces of mail delivered every day, even to the remotest parts of the world. If just one key factor went wrong with that system, . . . .

IF YOUR MIND STARTS TO GO, WILL YOU NOTICE?
By now you've realized that mail delivery is a crude metaphor for the human mind, the complexity of which makes the global postal network seem like a connect-the-dots picture by comparison. The mere act of reading and understanding the words on this page evokes whirlwinds of electrical activity and biochemical reactions in your brain - all needed for such subtle tasks as image analysis, pattern recognition, abstract thought, and memory storage (you are planning to cherish the memory of this article forever, aren't you?). And boggling your mind, which you did just moments ago, probably maxes out some of your circuits, with all neurons firing.

"Firing" is an apt term. We speak of the firing of neurons (nerve cells) when bits of information are transmitted from one such cell to the next. The ammunition consists of neurotransmitter molecules - infinitesimal "guided missiles" that zip across the synaptic junctions (the gaps between nerve endings), thereby completing that part of the circuit. What kind of information is transmitted, and how reliably it's transmitted, depends not only on the neural circuit being activated but also on the kind of missile being fired and the kind of target it seeks. If anything in this system becomes deficient, well, some of the light bulbs upstairs may start to flicker.

The irony is, you might not even notice it, because if your thinking capacity is slightly impaired, you just might not be thinking clearly enough to recognize the problem - and unrecognized problems tend to get worse. How's that for a vicious spiral?

ACETYLCHOLINE IS MUCH MORE THAN A NEUROTRANSMITTER
One way out of the spiral is by ensuring that your body has sufficient choline to produce abundant acetylcholine, a vital brain neurotransmitter that you've always taken for granted, just like the mail. But just as mail delivery slows down if the trucks run out of gas, your mind slows down if it's running low on acetylcholine (ACh for short). Actually, the analogy goes beyond that - and in a surprising way. Just as an organized society can't function without the materials and expertise needed to build its infrastructure (including the roads on which the mail travels), your body can't function without the acetylcholine needed for the proper functioning of its cells.


Choline is an essential "building
block" in the construction of
various types of cell membranes.

How's that, you say? Acetylcholine is the quintessential neurotransmitter - that's what "cholinergic function" is all about. It's not significantly active in non-neuronal systems, right? Not right, say some German pharmacologists who have reviewed the world's scientific literature to see what roles acetylcholine may play in non-neuronal function, i.e., in bodily organs or systems other than the central or peripheral nervous systems. Here is their eye-opening conclusion, in their own words ("phylogenetically" pertains to the evolutionary history of life on earth):1

. . . it becomes evident that the non-neuronal cholinergic system represents a most widely expressed and highly effective system created by nature to regulate or modulate basic cell functions. . . . It is fascinating to revise the role of ACh in biological systems by discriminating between non-neuronal and neuronal ACh. The non-neuronal cholinergic system, phylogenetically an extremely old system, is more widely distributed in biological systems than the neuronal system. The majority of human cells synthesize ACh . . . We postulate that a picture will emerge showing that ACh plays an important role in the regulation of cellular homeostasis, comparable with its dominant role within the nervous system.

The scientists are saying, in short, that we have long been overlooking a fundamentally important aspect of acetylcholine's role in our physiology - a role that runs deeper and broader than we imagined.

ACETYLCHOLINE HELPS MAINTAIN HOMEOSTASIS
Before getting to some of the evidence supporting the authors' conclusion, let's look at its implications. Homeostasis is one of the key concepts of biology. It is the process by which an organism, or an organ, or a single cell, maintains equilibrium by adjusting its physiological processes to compensate for the effects of disruptive outside forces, such as changes in temperature or chemical composition, or assault by hostile microorganisms. Since homeostasis is necessary for the proper functioning, and ultimately the survival, of our cells, it's fair to say that anything, such as acetylcholine, that plays an important role in that process is very important indeed. This suggests the obvious: that any nutritional precursor to such a vital compound - in this case, choline - should be high on our priority list.

An intriguing clue regarding the importance of ACh is its ubiquity in nature. Although we think of it primarily as a neurotransmitter, ACh is found, more than any other such type of molecule, in a wide variety of creatures - including those that do not even have a nervous system. It has been detected in bacteria and in primitive organisms, such as blue-green algae, yeasts, fungi, protozoa, worms, and sponges. It has also been discovered in some primitive plants.

ACETYLCHOLINE IS VITAL FOR CELLULAR FUNCTION
All of this suggests that ACh has played a vital role in the evolutionary history of life on earth, going back an astounding 3 billion years or so, and that this role, far from originating for purposes of neurotransmission, was much more basic than that, having to do with fundamental aspects of cellular development and function. When neuronal tissue did finally evolve in living things (marine organisms and mollusks) about 500 to 400 million years ago, it may be that these cells merely took advantage of an already sophisticated, built-in cholinergic system and adapted it to their newfound need for neurotransmission.

The German authors cite evidence of a role of ACh in such diverse non-neuronal cellular functions as mitosis (cell division), cell differentiation, organization of the cytoskeleton (the internal structural framework of the cell), cell-cell contact, secretion, absorption (of nutrients such as choline and amino acids), membrane development (especially choline-containing phospholipids); and metabolism.

Climbing the evolutionary tree: The mudskipper, a fish of Southeast Asia, spends more than half its time out of water. Long before fish even existed, acetylcholine was playing a vital role in the development of primitive life forms that had no nervous system.

EPITHELIAL CELLS ARE ESPECIALLY IMPORTANT
ACh appears to be synthesized in the majority of human cells, the authors report. A particularly important role of ACh in humans is in the function of epithelial cells. These are smooth, tightly packed cells that constitute the membranous lining, inside and outside, of most organs. They form the primary protective barrier against assault by potentially harmful substances, such as bacteria, viruses, and fungi, in their immediate environment. Epithelial cells are thus extremely important in maintaining homeostasis. They appear to be directly involved in regulation of the immune response, such as the release of antibodies to attack and destroy microbial invaders.

Acetylcholine activity has been detected in epithelial cells of the human airway, the alimentary tract, the kidneys, the urogenital tract, the eyes, the placenta, and the skin, as well as in glandular tissue of the female breast. And it has been observed that the vast majority of epithelial cells contain both nicotinic and muscarinic receptors, the same kinds of specialized molecular receptors that are activated by ACh in the nervous system. That cannot be a coincidence.

GALANTAMINE BOOSTS ACETYLCHOLINE
Nor can it be a coincidence that there is also widespread activity throughout the body of acetylcholinesterase (AChE), the enzyme that nature designed to attack and destroy ACh. The purpose is to preserve a proper physiological balance (an example of homoeostasis), but AChE sometimes gets the upper hand and depletes our ACh too much, thereby upsetting the balance. Because ACh deficiency is characteristic of Alzheimer's disease and other age-related cognitive impairments, the primary treatment is administration of agents that inhibit the action of AChE. One such agent is galantamine, a compound extracted from the snowdrop and daffodil, among other plants.

Note that, in the previous paragraph, we did not say AChE depletes our "stores" of ACh. That's because we don't have any stores of this vital molecule. ACh appears to be continuously released by cells - and wherever there is ACh, there is also AChE (inside the cells as well as outside), which is so efficient in its appointed task that the ACh can never get very far from its "home cell" before being gobbled up. This prevents it from being a true hormone (hormones are substances that can travel far from their point of origin before exerting their effects), but it has been called a "local hormone" because of the kinds of effects it has on its own turf.


Galantamine indirectly
boosts the available amounts of
ACh, but it goes a step further,
in a way that most other AChE
inhibitors do not.

GALANTAMINE DELIVERS
The nutrient choline, in addition to being a precursor to acetylcholine, is an essential "building block" in the construction of various types of cell membranes. It is believed that there is an interplay between these two functions, i.e., that either one may "target" the resources of the other in order to meet its needs. In any case, supplementing with choline is an excellent way to ensure that our bodies have ample access not only to good cell-building material but also to the acetylcholine they need for so many vital functions - non-neuronal as well as neuronal, as we now know. Important as well is pantothenic acid (vitamin B5), a cofactor for choline.

Galantamine indirectly boosts the available amounts of ACh, but it goes a step further, in a way that most other AChE inhibitors do not. Galantamine modulates nicotinic receptors (one of the two kinds of ACh receptors mentioned earlier) in such a way as to make them more sensitive - more receptive, in a sense - to ACh, thus boosting the efficacy of ACh and making galantamine that much more valuable as "brain food" forage-related cognitive impairments, and especially in the treatment of Alzheimer's disease.2

So if you're feeling somewhat less like the finely tuned, high-performance biological machine that you ought to be, don't go postal. Go get galantamine instead. When combined with choline and vitamin B5, special delivery of nutrients helps your mind and your body function better. And when the mailman comes with the package, don't let your dog bite him.

References

  1. Wessler I, Kirkpatrick CJ, Racke K. The cholinergic 'pitfall': acetylcholine, a universal cell molecule in biological systems, including humans. Clin Exp Pharm Physiol 1999;26:198-205.
  2. Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J, Albuquerque EX, Zerlin M. Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer's disease. Biol Psychiatry 2001;49:279-88.
  3. Coyle J, Kershaw P. Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic reeceptors: effects on the course of Alzheimer's disease. Biol Psychiatry 2001;49:289-99.

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