Galantamine Has Anti-Inflammatory Effect
Its systemic action is mediated by a
brain-to-spleen neural pathway—a surprising discovery
By Will Block
— Joseph Addison
In all thy humours, whether grave or mellow,
Thou’rt such a touchy, testy, pleasant fellow;
Hast so much wit, and mirth, and spleen about thee,
There is no living with thee, nor without thee.
ow did the spleen get such a bad reputation? It’s a nice, useful organ, nestled in an out-of-the way place, minding its own business, rarely causing trouble. And it never “vents.” So why do we associate it with ill temper? Who knows? In The Devil’s Dictionary, the often ill-tempered Ambrose Bierce had a bit of wicked fun with the spleen:
IN’ARDS, n. The stomach, heart, soul, and other bowels. Many eminent investigators do not class the soul as an in’ard, but that acute observer and renowned authority, Dr. Gunsaulus, is persuaded that the mysterious organ known as the spleen is nothing less than our immortal part. . . .
Mysterious indeed. Most people barely know they have a spleen, much less what it does. Even medical scientists, for a very long time, had little idea what it was for except to act as a kind of storage depot for blood. Well, we now know there’s a lot more to the spleen than that, including the fact that it’s a major component of our immune system—which is how it ties in with the subject of this article. (If you’re not conversant with your spleen, don’t get angry! You can get acquainted with it by reading the sidebar “Your Splendid Spleen.”)
Your Splendid Spleen
The American Heritage Dictionary says that the spleen is “a large, highly vascular lymphoid organ, lying in the human body to the left of the stomach below the diaphragm, serving to store blood, disintegrate old blood cells, filter foreign substances from the blood, and produce lymphocytes.”
There’s a lot packed into that definition. Vascular means packed with blood vessels. Lymphoid means pertaining to the system of vessels, nodes, and tissues that collect and circulate lymph throughout the body. Lymph is the clear, faintly yellowish fluid whose function is to transport white blood cells—mainly of the kind called lymphocytes—which are highly skilled soldiers (sort of like Special Forces) in our immune system army.
It’s more like a navy, actually. Lymphocytes float through the lymphatic system and the bloodstream until they detect chemical signals from tissues that need protection from some threat, such as harmful microbes. When such signals are received, and when the threat is correctly identified as a hostile agent (these are amazing tricks, biochemically speaking), the lymphocytes attack—everything from viruses to cancer cells. This is the “immune response” we often hear about. It’s not perfect, obviously, but without it, we would quickly die.*
So here is what the spleen (a fist-sized organ) does. It stores blood and regulates the number of erythrocytes (red blood cells) in the circulation. It breaks down old or damaged erythrocytes, disposes of the debris, and stores the iron contained in the erythrocytes for future use by stem cells in bone marrow, where new ones are made. It detects and destroys many blood-borne pathogens. And it produces lymphocytes and antibodies—proteins called immunoglobulins, which are produced in response to specific antigens (substances recognized by the body as a threat, provoking an immune response).
Whether or not you knew all that, you have probably heard about ruptured spleens. Even though it’s tucked beneath the rib cage, the spleen is still pretty vulnerable to injury, especially in car crashes. If the damage is great, surgical removal is sometimes required. When that occurs, the bone marrow and liver pick up some of the spleen’s duties, but a person without a spleen is more vulnerable to infections and must be extra careful to try to avoid them.
The spleen is the largest of the lymphoid organs, all of which are part of the immune system, a diverse collection of organs, tissues, and vessels that collaborate in keeping us safe from harm. In addition to the spleen, the immune system consists of: bone marrow; the thymus gland, where many white blood cells are produced; the lymphatic system; and the liver, tonsils, appendix, and groups of cells in the small intestine called Peyer’s patches.
In various times past, by the way, the term spleen was used to mean a whim or caprice, or even a state of melancholy. And for a long time, the spleen was seen as the seat of our emotions or passions. Hunh? What a stupid, crazy idea! Did those morons also think that bone marrow was the seat of our intellect? Sheesh!
What a splendid organ is the spleen. Too bad it’s gotten such a bum rap.
New Pathway Discovered
As for this article, it involves something with both a head (your brain) and a tail (your spleen), so to speak. In between is a neural pathway called the cholinergic anti-inflammatory pathway. It has been there forever, but it was discovered only recently—which is remarkable, considering that countless neuroscientists have been meticulously dissecting and analyzing the human nervous system for centuries. Yet there are still pathways to be discovered, which must give encouragement to budding young neuroscientists. And to physiologists, who seek to discover how everything in our bodies works to protect our health and keep us alive.
Foremost in protecting us is our immune system, a complex marvel of interacting cellular, molecular, and genetic systems designed to identify, attack, and destroy foreign invaders as well as native cells that have gone bad. There isn’t a general alive who wouldn’t be proud to command such an effective, multidisciplinary force, including molecular “spies” and “secret agents” whose missions could probably give novelists a run for their money.*
Galantamine Expands Its Repertoire
We’ll see what the cholinergic anti-inflammatory pathway is, and why it’s important, but first let’s cut to the chase and say that the plant alkaloid galantamine has now been discovered to be effective (in mice, anyway) against systemic inflammation. This common condition is believed to underlie or exacerbate many chronic degenerative diseases, such as cardiovascular and neurodegenerative diseases, cancer, and arthritis.
Galantamine, a nutritional supplement and, since 2001, a prescription drug now called Razadyne, has long been used as a safe and effective therapeutic agent against Alzheimer’s disease and its common precursor, mild cognitive impairment. Now, through galantamine’s apparent anti-inflammatory action, its medicinal repertoire may have expanded to include the whole body, not just the brain.
Inflammation—Good and Bad
Inflammation is a nonspecific defensive response to injury or infection. One of the first responses of the immune system to a nascent infection is inflammation. Without some degree of inflammation (even if it’s not perceptible), wounds and infections would not heal, and the affected tissues would continue to be damaged.
Inflammation that persists when the need for it has passed, however, causes damage of its own and can become a chronic systemic condition (often with no overt symptoms). This occurs when the body’s normally tight regulation of the inflammatory process is compromised. Thus, inflammation is a double-edged sword, being both a healthy response to acute injury and a potential cause of chronic injury.
Cytokines Are Messenger Molecules
Schematic of tumor necrosis factor-α, which contains 471 amino acids. The ribbons represent hydrogen-bonded β-pleated-sheet segments of the amino acid chain.
Inflammation is mediated by various kinds of compounds, such as eicosanoids and cytokines. The latter are a diverse group of hormonelike, cell-to-cell messenger molecules; most are proinflammatory, but some are anti-inflammatory. There are about 40 different kinds of human cytokines, interacting in complex and subtle ways in a “cytokine network.”
One cytokine of particular importance is a proinflammatory compound called tumor necrosis factor-α (TNF-α). This Dr. Jekyll & Mr. Hyde molecule can be either beneficial, as when it kills tumor cells, or harmful, as when it promotes excessive inflammation or even the formation of new tumors. (Such molecular “schizophrenia” is common in physiology.)
The (Not Las) Vagus Nerve
In the study cited above, scientists at the Feinstein Institute for Medical Research in Manhasset, New York, investigated the neurochemical mechanism underlying the cholinergic anti-inflammatory pathway, which they had discovered in 2000. This pathway represents a direct neural link between the brain and the immune system, something that had not previously been recognized. It involves the vagus nerve, which some scientists believe is the single most important nerve in the body.
Of the 12 cranial nerves (each of which is a pair of nerves, actually), the vagus nerve is number 10, and it’s the longest of them all. It’s a mixed nerve, meaning that it can transmit signals in both directions, from and to the brain. Arising from the sides of the medulla oblongata at the base of the brain, it passes through the neck and thorax into the abdomen, supplying nerve impulses to the tongue, pharynx, larynx, trachea, lungs, heart, and gastrointestinal tract, and extending as far as the second part of the transverse colon, where the colon touches the spleen.
A Surprising Connection
Obviously, the vagus is in the peripheral nervous system; it belongs to the parasympathetic part of the autonomic division of that system. It’s an extremely versatile nerve, providing motor impulses to both smooth muscle and cardiac muscle, as well as secretory impulses to glandular tissue. It’s responsible for such varied functions as slowing the heart rate, stimulating gastrointestinal peristalsis, and facilitating numerous muscle movements in the mouth (speech) and throat (breathing).
And, as has now been discovered (by the same research group), the vagus nerve provides a direct link from the brain to the spleen, via a previously unknown—and surprising—connection with the splenic nerve, which serves the spleen.
Kill the Messenger!
So, what does galantamine have to do with all this? Well, galantamine boosts the levels and activity of acetylcholine (ACh), which is an extremely important neurotransmitter in both the central and peripheral nervous systems. Nerves that depend primarily on ACh as their neurotransmitter are said to be cholinergic—and you can probably see what’s coming: the vagus nerve is cholinergic.*
That much has been known for many decades. What we now know, thanks to the New York researchers, is that when the vagus nerve is stimulated, either electrically or pharmacologically, the spleen’s output of the messenger molecule TNF-α is suppressed—which is a good thing, generally speaking, because overproduction of TNF-α is deleterious. (Kill the messenger!) Conversely, when the spleen’s TNF-α output is high, owing to bacterial infection or cytokine-mediated disease, vagus nerve activity is suppressed. Thus there is a connection between brain and spleen, and that connection is the cholinergic anti-inflammatory pathway.
Galantamine Counteracts Inflammation
It turns out that the activity of the cholinergic anti-inflammatory pathway is regulated by the brain’s level of activity of the enzyme acetylcholinesterase (AChE), which breaks down ACh. And galantamine is an AChE inhibitor, which accounts for its boosting of ACh levels.* The researchers found that administration of galantamine (via intraperitoneal injection) to mice that had been infected with a bacterial toxin stimulated the vagus nerve and dose-dependently suppressed the spleen’s output of TNF-α. It also conferred significant protection against the lethality of the infection.
Thus, galantamine had an anti-inflammatory effect—but demonstrating this fact was not the researchers’ objective in this study. It was, rather, to exploit the known biochemical mechanism of galantamine’s action on nicotinic acetylcholine receptors as a means of proving that the brain does, indeed, regulate the inflammatory response via its cholinergic action on the spleen. (We can skip the complicated details of how this was done.)
Where’s the Spleen?
In concluding one of their papers, the authors stated,
Galantamine is widely used in the treatment of cholinergic insufficiency and memory loss during Alzheimer’s disease, but the potential use of this agent for suppressing peripheral inflammation had not been considered previously. It is now plausible that pharmacologically targeting brain acetylcholinesterase to increase activity of the cholinergic anti-inflammatory pathway will suppress inflammation in diseases mediated by cytokines (e.g., rheumatoid arthritis, septic shock, and inflammatory bowel disease).
But they didn’t mention the spleen! Grrr.
- Pavlov VA, Parrish WR, Rosas-Ballina M, Ochani M, Puerta M, Ochani K, Chavan S, Al-Abed Y, Tracey KJ. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun 2008 [online preprint].
- Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, Chavan S, Tracey KJ. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci USA 2008;105(31):11008-13.
Alzheimer’s Angles: p53 Test and Turmeric
It seems that a tumor-suppressing protein called p53 has become a “hot topic” in research on Alzheimer’s disease (AD). That’s the view of Italian researchers who published a study advocating the development of better methods for early detection of AD, before clinical symptoms of the disease are manifest (by which time a great deal of neurological damage has already been done). They suggested that the measurement of p53 may constitute such a method.
They were not talking, however, about measuring normal p53, but rather, conformationally altered p53, i.e., p53 molecules whose tertiary protein structure has been denatured, or degraded to the unfolded state. This pathological condition has been found to be common in fibroblasts (cells that give rise to connective tissue) taken from AD patients. Using gene-sequencing methods, it’s possible to rule out mutations in the p53 gene as the cause of the protein denaturation, which means that some biochemical event associated with the disease itself is responsible.*
Naturally, you’re thinking, “But they found the defective p53 in AD patients, in whom clinical symptoms are, by definition, already evident. How does that constitute early detection?” It doesn’t, but there is reason to believe, from other experiments, that the denaturation of p53 is an early event caused by low concentrations of the soluble form of amyloid-beta, the protein whose eventual aggregation into insoluble plaques is one of the neuroanatomical hallmarks of AD.
Other experimental evidence, obtained with blood cells, suggests that the p53 test could have a high level of sensitivity (about 90%) for AD and that it could allow AD to be distinguished readily from other dementias, such as the dementia associated with Parkinson’s disease, and from normal aging. Owing to its early detection capability, the test might also be useful in diagnosing mild cognitive impairment, the common precursor to AD.
In their paper, the authors also discussed the need for safe, effective interventions in AD, particularly those derived from natural products, such as herbs and spices. They pointed to the growing body of research indicating that turmeric is especially beneficial in this regard, owing to the strong anti-inflammatory and antioxidant properties of the curcumin and related curcuminoids it contains. They stated,
Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, AD, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis.
Curcumin Improves Learning and Memory
A recently published study in China has added to the body of evidence supporting the use of turmeric in AD. In this study, 40 female mice were treated for 90 days with aluminum chloride and D-galactose to induce an AD-like condition. For the last 45 days of that period, the test mice also received curcumin, whereas the controls did not. Subsequent cognitive testing of the mice showed that learning and memory were significantly improved with curcumin, which also attenuated the disease-associated changes in their brains.
Similarly positive results were obtained with cultured rat cells that had been treated with aluminum chloride to make them susceptible to apoptosis (programmed cell death). Curcumin maintained the cells’ viability by providing significant protection from cellular damage.
- Racchi M, Uberti D, Govoni S, Memo M, Lanni C, Vasto S, Candore G, Caruso C, Romeo L, Scapagnini G. Alzheimer’s disease: new diagnostic and therapeutic tools. Immunity Ageing 2008 [online preprint].
- Pan R, Qiu S, Lu D, Dong J. Curcumin improves learning and memory ability and its neuroprotective mechanism in mice. Chin Med J 2008;
Will Block is the publisher and editorial director of Life Enhancement magazine.