The Antiinflammatory Use of Galantamine and Choline

Foiling Cytokine Storms
with Cholinergics

The α7 nicotinic acetylcholine receptor plays a substantial role in
mediating the inflammatory effects of proinflammatory cytokines.

By Will Block

B iomedical scientists are in significant agreement that inflammation is at the root of many deadly diseases, including those as diverse as heart disease, cancer, chronic lower respiratory diseases (such as COPD and asthma), Alzheimer’s disease, diabetes, influenza, and pneumonia. More than just related to inflammation, these diseases have been linked to runaway cytokine-mediated inflammation (aka cytokine storms). This phenomenon is how the Ebola virus kills its victims.

A recent paper, in agreement with the “inflammation at the root theory,” suggests that cytokine-based therapeutic agents may play a major role in the treatment of the above diseases.1 Cytokines are small proteins released by cells that operate as inflammation triggers and responders to infections. The researchers — based at the Medical College of Georgia in Augusta, GA and Targacept, a research firm in Winston-Salem, NC — note that the mechanisms of various cytokines are still inadequately understood. In fact, most research to date has concentrated on the inhibition of specific cytokines, such as tumor necrosis factor alpha (TNF-α).

Inflammation is at the root of many
diseases: heart disease, cancer,
chronic lower respiratory diseases
(including COPD and asthma),
Alzheimer’s disease, diabetes,
influenza, and pneumonia.

The Importance of Keeping Immune Function Strong

Nonetheless, several recent preclinical studies show that the α7 nicotinic acetylcholine receptor plays a substantial role in mediating the inflammatory effects of proinflammatory cytokines. Such an approach, if validated by clinical research, would go a long way toward maintaining and even resuscitating immune function under extremely stressful conditions, such as those caused by lethal viruses.

Cholinergic Anti-Inflammatory Pathway

Figure 1. Stimulation of the vagus nerve provokes release of acetylcholine (ACh) that binds to α7 nicotinic ACh receptors on macrophages and leads to decreases in local and systemic levels of tumor necrosis factor (TNF).
(click on thumbnail for full sized image)

Discovered only in 2001,2 the cholinergic anti-inflammatory pathway regulates the immune system through cholinergic mechanisms that act on α7 receptors expressed on macrophages and immune cells (see Fig. 1). If the preclinical findings translate into human efficacy, this approach could provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components. Among these diseases would be Alzheimer’s disease and possibly deadly viruses such as Ebola.

Ebola Fatalities Result from Cytokine Storms

The terrible damage that the Ebola virus does to the body results, in its final throes, in leaky blood vessels, which dramatically reduce blood pressure, lower body temperature severely, and plummet the system into shock.

However, there is something else when you examine the details of Ebola’s endgame. It’s not the virus itself that kills you; it’s the overreaction of your immune system. When your immune system is working well, infections are eliminated. But if it is overworking at runaway levels, it creates immense debilitating damage. Think of a runaway train, where the overworking of the engine so exceeds its capacity that it blows up and ultimately leaves the tracks.

It’s not the Ebola virus that kills you;
it’s the overreaction of your
immune system

The most extreme form of a runaway immune attack is the cytokine storm, when acute inflammation results in multiple organ shutdowns, and the system can no longer function. The cytokine storm is a belligerent immune response characterized by the recruitment of inflammatory leukocytes and extravagant levels of cytokines and chemokines at the site of infection.

Over the past decade, humanity has been living on the edge of not one, but five brand new pandemics: Severe Acute Respiratory Syndrome (SARS) that peaked in 2003; H5N1 (bird flu) influenza in 2005 and 2006; H1N1 (swine flu) in 2009; Middle East Respiratory Syndrome (MERS) in 2012; and Ebola Virus Disease (EVD) in 2014. Of these, SARS, H5N1, H1N1, and EVB kill by cytokine storms.3 MERS may also use cytokine storms as its ultimate weapon for the destruction of life.4

Vitamin D for Cytokine Storms

To understand the potential for the cholinergic anti-inflammatory pathway it is worth revisiting the way in which vitamin D works to quell cytokine storms. According to Durk Pearson & Sandy Shaw (see “Defending Yourself Against Virus Infections in their Life Extension News, in the July 2009 issue of this publication):

At the same time that vitamin D stimulates expression of genes that create antimicrobial peptides, [vitamin D] is also reported to “dampen certain arms of the adaptive immune system, especially those responsible for the signs and symptoms of acute inflammation, such as the cytokine storms operative when influenza kills quickly.” Hence, vitamin D acts as both an immune stimulant and an anti-inflammatory. In relation to seasonality and vitamin D’s suppression of killer cytokine storms, the first wave of the 1918 influenza (A/M1N1) pandemic in the spring was mild, whereas 6 months later in fall and winter, there was a second wave with much higher mortality. (Reference removed; emphasis added.)

As indicated above, there are a number of viruses, including bird flu and SARS, that can trigger this rapid dominance assault — the cytokine storm — but Ebola definitely takes the lead. Imagine that you hired a team of guards to prevent intruders’ access to your home and the guards went out into the street and surrounding community and started killing everyone. That’s clearly an out-of-control system, and ultimately dangerous to you, especially when your access to supplies is cut off. Who would deliver food (or anything) to such a neighborhood? Even though you had initiated the protection service, would you venture outside expecting to be spared? This would be a rapid dominance assault.

There are a number of viruses,
including bird flu and SARS, that can
trigger this rapid dominance assault
the cytokine storm—but Ebola
definitely takes the lead.

Galantamine for Cytokine Storms

Figure 2. The activation of the cholinergic anti-inflammatory pathway reduces the inflammatory response. These effects are mediated through engagement of α7-nicotinic acetylcholine receptors (α7 nAChRs). Acetylcholine is released following vagus-nerve stimulation, resulting in inhibition of the synthesis and release of pro-inflammatory mediators.
(click on thumbnail for full sized image)

Do acetylcholinesterase inhibitors (AChEI) have both immune stimulant and anti-inflammatory properties? A paper published in 2009, adhering to the “inflammation at the root theory,” states that, “The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases.”5 Continuing, the researchers explain that recent advances in understanding cytokine toxicity have led to the discovery of the cholinergic anti-inflammatory pathway. This pathway is defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the α7 subunit-containing nicotinic acetylcholine receptor (α7 nAChR) (see Fig. 2). Thus α7 nAChR can help prevent the damaging effects of cytokine overproduction. Among all the common AChEI’s, only galantamine is also a positive allosteric modulator of α7 nAChR.

Dietary Fat Activates the Cholinergic Anti-Inflammatory Pathway

Another study6 shows that dietary fat can activate the cholinergic anti-inflammatory pathway, a finding that may help explain the immune system’s failure to react to food antigens and commensal bacteria (a symbiotic relationship between two organisms of different species in which one derives some benefit while the other is unaffected). In this paper, Kevin J. Tracey, MD, Professor, Molecular Medicine & Neurosurgery, Hofstra North Shore-LIJ School of Medicine, investigated the potential implications for dietary intervention in the treatment of inflammatory diseases. The brain and its neural networks control the vagus nerve regulation of peripheral functions. Nonetheless, little was known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway (see Fig. 2). Dr. Tracey reported that brain acetylcholinesterase (AChE) activity controls systemic and organ specific TNF-α production during endotoxemia, the presence of endotoxins in the blood, which may result in shock. AChE is an enzyme that breaks down the neurotransmitter acetylcholine (ACh).

Recent advances in
understanding cytokine toxicity
have led to the discovery of the
cholinergic anti-inflammatory

Galantamine’s Anti-Inflammatory Activity Depends on α7 nAChR

Administration of galantamine, an AChEI, significantly reduced TNF-α through vagus nerve signaling, and protected against lethality during murine endotoxemia. However, administration of a centrally acting muscarinic receptor antagonist — the other acetylcholine receptor, more sensitive to muscarine rather than nicotine — abolished the suppression of TNF-a by galantamine.5 This indicates that suppressing AChE activity along with central muscarinic receptors controls peripheral cytokine responses.

Also, administration of galantamine to α7 nAChR knockout mice (without any α7 nAChR activity) failed to suppress TNF-α levels, thus indicating that the α7 nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine.5

These findings show that the inhibition of brain AChE suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7 nAChR-dependent mechanisms.5 The data also indicate that a clinically used centrally-acting AChEI can be utilized to suppress abnormal inflammation to therapeutic advantage.

Defeating Low-Grade Inflammation with Galantamine

Then, in 2011, dual-function galantamine — AChEI and modulator of α7 nAChR — significantly reduced serum TNF-α levels through vagus nerve signaling, and protected against lethality during endotoxemia in mice.7

This work was performed at the Feinstein Institute for Medical Research where Dr. Tracey is Editor Emeritus. The researchers note that obesity is associated with low-grade inflammation, which in turn helps cause some of its adverse consequences. In previous work, they demonstrated that the cholinergic agent galantamine suppresses excessive proinflammatory cytokine release. In fact, galantamine treatment of obese mice significantly reduced body weight, food intake, abdominal adiposity, plasma cytokine and adipokine levels, and significantly improved blood glucose, insulin resistance and hepatic steatosis (aka, fatty liver, the collection of excessive amounts of triglycerides and other fats inside liver cells.).

The α7 nAChR-mediated
cholinergic anti-inflammatory
pathway is required for the anti-
inflammatory effect of galantamine.

In addition, galantamine alleviated impaired insulin sensitivity and glucose intolerance significantly. These results indicate a previously unrecognized potential of galantamine in alleviating obesity, inflammation and other obesity-related complications in mice. These findings indicate the efficacy of natural galantamine in the context of human obesity and metabolic syndrome.

What About Choline?

Evidence shows that ACh plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway.”8 Because choline is a precursor to the production of ACh in the brain and elsewhere in the body, choline must therefore play an important role in inhibiting cytokines under moderate and acute circumstances.

JAK-STAT Anti-Inflammatory Pathway

As understanding of the cholinergic anti-inflammatory pathway from the central nervous system to the macrophage defense system has been clarified, advances have also been made in delineating the molecular mechanisms involved.6 For example, the neuroprotective effects of α7-selective binding molecules can be traced to α7 activation and transduction of signals to various kinases via JAK2 (Janus kinase 2), all of which participate in a key cell survival pathway. A kinase is a type of enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates, molecules upon which enzymes act. This process is known as phosphorylation.

JAK-STAT and Cholinergic Anti-Inflammatory Pathways Work Together

Figure 3. Activation of the vagus nerve leads to the release of acetylcholine (ACh) that binds to α-7 nicotinic receptors (α7 nAChR) on cytokine producing cells. This inhibits the activation of NF-κB and activates STAT3 phosphorylation. Phosphorylated STAT3 triggers an antiinflammatory signal by increasing suppressor of cytokine signaling 3 (SOCS3) expression, which suppresses signaling from cytokine receptors. Together, these signals prevent the release of TNF-α, HMGB1, and other cytokines implicated in the pathogenesis of inflammatory disease.

Tracey KJ. Fat meets the cholinergic antiinflammatory pathway. J Exp Med. 2005 Oct 17;202(8):1017 – 21.

(click on thumbnail for full sized image)

The JAK-STAT anti-inflammatory pathway works in tandem with the cholinergic anti-inflammatory pathway to help modulate inflammation.6 So-called “immune precipitation” experiments indicate that the α7 receptor and JAK2 interact directly (see Fig. 3). The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second messenger system, which trigger physiological changes such as proliferation, differentation, migration, survival, and apoptosis. The JAK-STAT system consists of three main components: 1) a receptor; 2) Janus kinase (JAK); and 3) Signal Transducer and Activator of Transcription (STAT).

Endotoxins Cause Strong Immune Responses

Other studies have examined the effects of nicotine on lipopolysaccharide (LPS)-treated and control peritoneal macrophages and found that nicotine treatment leads to phosphorylation of STAT3, another key component of the cellular antiapoptotic cascade. LPSs are endotoxins that elicit strong immune responses. This nicotine-mediated phosphorylation is inhibited by the α7-selective antagonists, as well as by a selective inhibitor of JAK2 phosphorylation.

STAT3 Critical for Cholinergic Anti-Inflammatory Pathway

Immune precipitation studies illuminate previous findings showing that nicotine exposure recruits JAK2 and leads to an increased association between JAK2 and α7 receptors.9 When mice were examined whose macrophages were deficient in STAT3—unlike other STATs, STAT3 readily opens up new avenues through which STATs may regulate the cell—researchers found that vagus nerve stimulation did not reduce peritoneal (the lining of the abdominal cavity) cytokine levels or intestinal inflammation as it does in control animals. These data support the interaction of JAK2 and α7 and the critical role of STAT3 in the cholinergic anti-inflammatory pathway.

Galantamine and choline
supplementation can help you gain a
cornucopia of advantages that include
memory preservation and
enhancement as well as the benefits
of honing your immune system.

Returning to our opening paper,1 LPS-stimulated release of TNF-α and macrophage inflammatory proteins is inhibited by low concentrations of nicotine. Nicotine, because of its effect on α7 receptors, has anti-inflammatory benefits, however bad some of its other effects might be. Nicotine also inhibits LPS-stimulated IκB phosphorylation, thereby preventing NF-κB activation (see Fig. 3), which is necessary for gene transcription of proinflammatory mediators. IκB is a kinase enzyme complex that is involved in propagating the cellular response to inflammation. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA.

Cholinergic Anti-Inflammatory Pathway Knowledge

Understanding the cholinergic anti-inflammatory pathway and its role in mitigating inflammation and disease continues to grow, and it is clear that α7 and other nicotinic receptor subtypes play a prominent role. There are numerous reports that nicotine inhibits LPS-stimulated phosphorylation of the cytoplasmic inhibitory protein I-κB, thereby preventing NF-κB activation, which is necessary for gene transcription of proinflammatory mediators.

Moreover, anti-inflammatory effects mediated by α7 nicotinic receptors can be synergistic with other signaling systems such as steroids. Indeed, for those novel α7-selective ligands (binding molecules) that have been tested to date, there appear to be consistent anti-inflammatory effects.

Galantamine and Choline: Anti-Inflammatories

In your arsenal of supplements to defend against influenzas and other viruses, it will be a good idea to add galantamine and choline, if you haven’t done so already. Then you can gain a series of benefits that include memory preservation and enhancement as well as the benefits of honing your immune system.


  1. Bencherif M, Lippiello PM, Lucas R, Marrero MB. α7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci. 2011 Mar;68(6):931 – 49.
  2. Tracey KJ, Czura CJ, Ivanova S. Mind over immunity. FASEB J. 2001 Jul;15(9):1575 – 6.
  3. Oldstone MB, Teijaro JR, Walsh KB, Rosen H. Dissecting influenza virus pathogenesis uncovers a novel chemical approach to combat the infection. Virology. 2013 Jan 5;435(1):92 – 101.
  4. Lau SK, Lau CC, Chan KH, et al. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol. 2013 Dec;94(Pt 12):2679 – 90.
  5. Pavlov VA1, Parrish WR, Rosas-Ballina M, et al. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun. 2009 Jan;23(1):41 – 5.
  6. Tracey KJ. Fat meets the cholinergic antiinflammatory pathway. J Exp Med. 2005 Oct 17;202(8):1017 – 21.
  7. Satapathy SK, Ochani M, Dancho M, et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med. 2011;17(7 – 8):599-606.
  8. Pohanka M. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity. Int J Mol Sci. 2014 Jun 2;15(6):9809 – 25.
  9. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, van den Wijngaard RM, Boeckxstaens GE. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol. 2005 Aug;6(8):844 – 51.

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

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