Nervous System Starts and Stops the Inflammation Not Only In Psoriasis

Inflammation? Forget about the immune system… It is all about the cholinergic anti-inflammatory pathway!

It is not the immune system what tells the immune cells what to do…

It is actually impossible because immune cells are the part of the immune system so how could part of (something) immune system could tell itself what to do?

Sure, immune cells cooperate and communicate but they must have and do have some “boss” – it is the nervous system.

Nervous system controls the development of all organs and parts of the body. Subsequently during our lives it is the nervous system which often lacks as a result of stress, bad diet, malnutrition and infections.

These negative effects of environment are the underlying cause of various health problems and symptoms. Virtually all chronic health problems are accompanied by inflammation and actually the “Inflammation Causes The Symptoms We Call Diseases”.

Yes, it is mostly the inflammation what hurts us not the underlying problem itself.

Before you continue reading this article I recommend you to watch the next video where Dr. Kevin Tracey explains his work in easy to understand way during his TEDMED presentation:

Vagus nerve, TNF-alpha and alpha-7 nicotinic acetylcholine receptor connection

The alpha-7 nicotinic acetylcholine receptor strongly affects the inflammation and anti-inflammatory pathways as you already know.

The powerful effects of TNF as major inflammatory molecule produced by the body are summarized in the next abstract of the study “Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation” published in Nature in 2003.


Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the ‘cholinergic anti-inflammatory pathway’ has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
” [4]

The immune system has always the reason why it activates and starts the inflammation. Macrophages and neutrophils do not turn themselves against the own body – NEVER. And all those “autoimmune” diseases are not really autoimmune without some existing underlying cause – usually bacterial, viral or fungal infection but also due to chemical toxicity.


The innate immune system is activated by infection and injury to release pro-inflammatory cytokines, which activate macrophages and neutrophils and modulate specific cellular responses. The magnitude of the cytokine response is critical, because a deficient response may result in secondary infections, while an excessive response may be more injurious than the original insult.
” [5]

The researchers found out that vagus nerve which controls major organs (like heart, lungs and digestive tract) and important muscles in the body is capable of regulation of the inflammatory response. It is very effective in induction and suppression of inflammation which can be very localized like it surely is in case of psoriasis where clearly just some spots on the skin are red, scaly and inflamed.

If autoimmunity against the skin were the real cause of psoriasis there would be all 100% of the skin red and scaly.


Efferent signals in the vagus nerve provide a direct mechanism for neural regulation of the immune response that is rapid, localized, and integrated. Vagus nerve stimulation inhibits the release of TNF, HMGB1, and other cytokines, and protects against endotoxemia and ischemia-reperfusion injury.
” [5]

It took some time for the scientists to identify the exact mechanism behind the stimulation and suppression of inflammation by nervous system. And not so long ago the alpha-7 nicotinic acetylcholine receptors were identified as the major group of receptors regulating the inflammation.

Activation of the alpha-7 nicotinic acetylcholine receptors strongly suppresses the inflammation.

You may help the body to activate the receptor with agonists which are choline (a major component of lecithin). Body uses choline to produce acetylcholine which is a neurotransmitter and activates the anti-inflammatory alpha-7 nicotinic acetylcholine receptor as well.

Another strong activator of alpha-7 nicotinic acetylcholine receptor is nicotine which should not be the first line of defense against the excessive inflammation but still it is an option.


The alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF…

Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural alpha7nAChR agonist.
“[6]

The researchers found out that choline dose-dependently suppressed the TNF release from endotoxin-activated macrophage-like cells in mice. This effect was also associated with significant inhibition of NF-kappaB – a protein which is heavily involved in inflammatory response.

In genetically engineered mice which lacked the functional alpha-7 nicotonic acetylcholine receptor choline administration failed to prevent the TNF production.


In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires alpha7nAChR-mediated signaling.
” [6]

The dose of choline which significantly inhibited the TNF release was 50 mg/kg administered intraperitoneally.

Cholinergic anti-inflammatory pathway – inflammation is controlled by nervous system

You can read about the effects of Ephedrine, Nicotine and Galantamine on inflammation in my previous post “How Ephedrine, Galantamine and Nicotine treat Inflammation in Psoriasis”.

Inflammation is also a target of drugs in cases of acute and chronic CNS disorders.[1]

If you still doubt about the nervous system as a master regulator of inflammation the next lines will convince you.

You probably don’t know about the Cholinergic Anti-Inflammatory Pathway which you can read about in short on Wikipedia.

Here I will explain it to you in a very easy way so hopefully you will understand most of it. If you had any questions please feel free to ask them in the comments under the blog post.

The next two images presents the same thing but there are some differences. The first picture includes the spleen but omits the Nicotine and the second picture does not depict the spleen but involves the role of Nicotine and Vagus Nerve stimulation.

But as I said above both pictures describes the same thing – cholinergic anti-inflammatory pathway.

As you can see endotoxins (lipopolysaccharides), uric acid and interleukin-1 alpha may induce the inflammation. On the other hand acetylcholine, spleen and alpha-7-nicotinic acetylcholine receptor are involved in attenuation of inflammatory response.
Image Source: “Neural circuitry of the inflammatory reflex”.
Kevin J. Tracey. Reflex control of immunity. Nat Rev Immunol. 2009 Jun; 9(6): 418–428.

 

cholinergic_antiinflammatory

“The inflammatory response to microorganisms, and ways of controlling it.”
“Clockwise from lower right: many bacteria contain lipopolysaccharide in their cell walls, which stimulates macrophages. These immune cells then make and release various cytokine (‘alarm’) molecules, including tumour-necrosis factor (TNF) and interleukin-1. But too much TNF in the blood can be harmful, leading to excessive inflammation and septic shock. Several drugs (orange boxes) inhibit steps in TNF synthesis. In addition, Tracey and colleagues have found that when the vagus nerve detects interleukin-1 (left), it releases acetylcholine (right), which binds to the a7 receptor2 on macrophages and inhibits cytokine production. This suggests possible new ways of controlling inflammation: through electrically stimulating the vagus nerve, by acupuncture, or with the use of nicotine (which mimics acetylcholine). “
Image and Text Source: Claude Libert. Inflammation: A nervous connection. Nature 421, 328-329 (23 January 2003)

The circle in the picture above starts bottom right with lipopolysaccharide (endotoxins). The same endotoxins which I always talk about on this blog. The endotoxins may come from small intestine (in case the bile flow lacks), infected teeth (including the dead teeth with root canals) or less often from some other source of infection.

And what role do adrenal glands play in this inflammation?

We all know that glucocorticoids are very effective in cooling off the inflammation.

There are two possible causes why we develop the inflammation like it is present in psoriasis:

  • weak adrenal glands (chemically or physically damaged, dysregulated, infected,…)
    or
  • the source of inflammation is so serious that natural inflammatory response overwhelms the anti-inflammatory effects of normal levels of glucocorticoids.

The result of weak adrenals is low levels of glucocorticoids which are anti-inflammatory.

High levels of glucocorticoids may suppress the immune system to the point of allowing the invasion of opportunistic infections. On the other hand too strong immune reaction may cause massive tissue damage (which we can see in all those chronic degenerative inflammatory diseases), or even septic shock and death.

Inflammatory response of the body should be balanced in order to resolve the problem and keeping the undamaged tissues without any harm. If the body lacks in inflammatory response we can develop various infections. If the the inflammatory response is too strong then the inflammation damages also the healthy tissues and leads to various symptoms – psoriasis, psoriatics arthritis and many others diseases which are often falsely called “autoimmune diseases”.
Image source: Kevin J. Tracey. Reflex control of immunity. Nat Rev Immunol. 2009 Jun; 9(6): 418–428.

Hopefully, this was the easy to understand explanation of cholinergic anti-inflammatory pathway. If you are interested in detailed understanding of Inflammatory Reflex and Cholinergic anti-inflammatory pathway you can read “Cholinergic control of inflammation” or “Reflex control of immunity” articles from Kevin J. Tracey for free.

Modulate the cholinergic anti-inflammatory pathway naturally

Nicotine is not the only one natural molecule besides choline which can modulate the cholinergic anti-inflammatory pathway.

The easiest and safest way how to decrease the excessive production of inflammatory cytokines is Galantamine. I have mentioned the Galantamine a lot of times on this blog.

Galantamine is not the cheapest product due to the fact that it is popular (for purposes of lucid dreaming) and is sold also as a prescription drug for Alzheimer’s disease.

Galantamine is not the agonist (activator) of anti-inflammatory alpha-7 nicotinic acetylcholine receptor but it is its positive allosteric modulator.

What does it mean?

It means that galantamine will bind to some other receptor of the cell but this will result in amplified effect of agonists (activators) like acetylcholine or nicotine on alpha-7 nicotinic acetylcholine receptor.

Positive allosteric modulator either increases the binding affinity of agonist or improves the functional efficacy of the agonist. This means that Galantamine helps initiate the stronger anti-inflammatory response upon activation of alpha-7 nicotinic acetylcholine receptor by choline, acetylcholine or nicotine.

I wrote more about alpha-7 Nicotonic acetylcholine receptor in my previous posts:
“How Ephedrine, Galantamine and Nicotine treat Inflammation in Psoriasis” and “Nicotine cleared up psoriasis”.

 

References:

1) Stuart M Allan and Nancy J Rothwell. Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci. 2003 Oct 29; 358(1438): 1669–1677.
2) Kevin J. Tracey. Reflex control of immunity. Nat Rev Immunol. 2009 Jun; 9(6): 418–428.
3) M. Rosas-Ballina and K. J. Tracey. Cholinergic control of inflammation. J Intern Med. 2009 Jun; 265(6): 663–679.
4) Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003 Jan 23;421(6921):384-8.
5) Czura CJ, Friedman SG, Tracey KJ. Neural inhibition of inflammation: the cholinergic anti-inflammatory pathway. J Endotoxin Res. 2003;9(6):409-13.
6) Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, Ochani M, Ochani K, Yang LH, Hudson L, Lin X, Patel N, Johnson SM, Chavan S, Goldstein RS, Czura CJ, Miller EJ, Al-Abed Y, Tracey KJ, Pavlov VA. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol Med. 2008 Sep-Oct;14(9-10):567-74.



2 Responses

  1. Andrew Thaxton says:

    Is there a source of galantamine/snowdrop herbs that you can recommend? What about choline? Should these (lecithin?) be supplemented together? Thank you for producing this blog.

    • John says:

      iHerb has only one brand of galantamine – the product called Galantamind. Its price is currently about 112 USD for 90x8mg capsule.

      From Amazon I would try this Galantamine from Relentless Improvement. Its price is currently at 32 USD for 90x4mg tablet.

      The patients with Alzheimer’s disease take up to 24mg daily in divided doses but I think it is too much for our purposes because you can definitely feel “something” in your head even at 8mg dose. So higher dosages may not get you a pleasant feeling in the head. It is a feeling like inability to clear thinking and focus even though you can focus.

      Sure, choline and galantamine may be taken together.

      Choline or soy or sunflower lecithin should potentiate the anti-inflammatory properties of galantamine so it is better to start with low dosages of both supplements when combined.

      It is advised not to take galantamine and choline before sleep due to its effects which may cause lucid dreaming.

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