Acetylcholine

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Acetylcholine is a neurotransmitter that is thought to play a role in many human diseases including myalgic encephalomyelitis and postural orthostatic tachychardia syndrome.

Function[edit | edit source]

Acetylcholine is used in the autonomic nervous system, both as an internal transmitter for the sympathetic nervous system and as the final product released by the parasympathetic nervous system. It plays an important role in regulating the inflammatory response and is used at the neuromuscular junction by motor neurons in order to activate muscles.

In the central nervous system, acetylcholine modulates arousal and temperature regulation, is important for attention, memory and motivation, and may play a role in central fatigue.

General Function Summary[edit | edit source]

As a neurotransmitter, acetylcholine is produced in nerve cells. Any cell that produces or is affected by acetylcholine is called cholinergic. In the nervous system, acetylcholine typically travels from the axon to the dendrite of the next nerve cell across the synaptic cleft. In muscle cells, it travels to the receptors on the muscle fiber, called the motor end plate. Acetylcholine can activate receptors, such as the nicotonic receptors or muscarinic receptors. These receptors can also be activated by, or blocked by, other molecules such as nicotine and muscarine. Muscarinic receptors are typically found in the parasypathetic nervous system, whereas nicotonic receptors are found in the central nervous system, peripheral nervous system, and neuromuscular junctions. Nicotonic receptors are classified as ligand-gated ion channels - when activated they open and allow ions like K+, Na+, and Ca+ to move in or out of the cell. Muscarinic receptors exert their effects on cells via a secondary messenger system.

Closing of the gate is completed by Acetylcholinesterase ( AChE) which catalyzes the breakdown of acetylcholine into choline and acetic acid, which allows the ion gate to close. Each molecule of AChE can degrade about 25,000 molecules of acetylcholine (ACh) per second. If the AChE molecule is blocked, breakdown of ACh will not be completed and the gate will remain open. If the AChE is blocked on a muscle fiber, the fiber will remain contracted.[1] Various duration and strength AChE blockers exist. Short-duration or reversible AChE blockers have been developed as medications, as short-term blocking of AChE can allow the ion gates to stay open longer and increase ACh availability. Long-duration and irreversible AChE blockers, including Nerve Gas, can cause various symptoms up to and including paralysis and death. [2]

Immune system[edit | edit source]

The vagus nerve speaks directly to the immune system via acetylcholine.[3][4][5]

Acetylcholine plays a role in innate immunity through nicotinic acetylcholine receptors and in the adaptive immune response via M3 muscarinic acetylcholine receptors (M3R).[6]

Muscarinic receptors[edit | edit source]

Knockout mice, that is mice lacking the gene that encodes for M3R, had impaired response to bacterial infection, while normal mice given a muscarinic agonist (to increase the activity of M3R) had enhanced production of IL-13 and IFN-γ.[7] Another study used a muscarinic agonist and an antagonist (reduce activity) and found antagonist suppressed the immune response while the agonist exaggerated it.[8]

Mast cells[edit | edit source]

Several studies suggest a relationship between autonomic nervous system dysfunction and mast cell activation via acetylcholine.

One study found that acetylcholine via muscarinic receptors strongly inhibited the release of histamine in mucosal mast cells.[9] The activity of acetylcholinesterase, an enzyme that breaks down acetylcholine, was found to be significantly increased in 64% of patients experiencing flares of ulcerative colitis.[10]

In human disease[edit | edit source]

Myasthenia Gravis[edit | edit source]

Autoantibodies to acetylcholine receptors alpha subunit have been found in patients with myasthenia gravis. These cross react with herpesvirus glycoprotein D. [11] Antibodies to acetylcholine receptor and HSV-1 antigens crossreact.[12]

B cells from myasthenia gravis patient stimulated in vitro by Epstein-Barr virus (EBV) produced acetylcholine autoantibodies.[13] Ongoing EBV infection of the thymus has been posited as a causative agent for the production of aceytlcholine receptor autoantibodies in myasthenia gravis.[14][15]

Sjögren's syndrome[edit | edit source]

Autoantibodies against muscarinic acetylcholine receptor on exocrine glands were found in patients with Sjögren's syndrome.[16]

Chronic fatigue syndrome[edit | edit source]

Since at least the 1990s it has been theorized that CFS might be associated with abnormalities of acetylcholine neurotransmission. To test this hypothesis, a provocation study was performed using the acetylcholinesterase inhibitor pyridostigmine. The results did indicate that CFS patients' hypothalamuses are hypersensitive to cholinergic stimulation relative to matched healthy controls. [17] These results mirror similar, highly replicated findings showing that CFS patients' hypothalamuses are hypersensitive to serotonergic stimulation as well (see Buspirone challenge test).

A 2003 study of 60 CFS patients found that 53.3% had detectable autoantibodies against the M1 muscarinic acetylcholine receptor. [18] In 2015, a large German study found 29% of ME/CFS patients had elevated autoantibodies to M3 and M4 muscarinic acetylcholine receptors, as well as ß2 adrenergic receptors.[19][20] A 2016 Australian study found that ME/CFS patients had significantly greater numbers of single nucleotide polymorphisms associated with the gene encoding for M3 muscarinic acetylcholine receptors.[21]

Several small clinical trials have been performed to assess the benefit of treatment with acetylcholinesterase inhibitors in CFS; one using pyridostigmine [22] and another using galantamine. [23] Both trials showed improvement of symptoms on the treatment. The exact mechanism or mechanisms by which AChE inhibition might help in CFS are unclear due to how widely represented acetylcholine-responsive tissues are in the brain, (neuro)musculature, cranial and pre-ganglionic spinal autonomic nerves, vasculature, and peripheral C-fibers. Additionally, AChE inhibitors such as pyridostigmine are able to stimulate growth hormone secretion, and both CFS and POTS patients have been shown to have disturbed growth hormone levels. [24][25][26]

Anecdotally, some ME/CFS patients have tried pyridostigmine (trade name Mestinon), with some success.[27] A work in progress study of exercise intolerance in preload failure found that Mestinon improved exercise tolerance, but the study has not yet been published.[28]

Postural orthostatic tachycardia[edit | edit source]

A small study of postural orthostatic tachycardia syndrome in children found that 24.39% of patients had acetylcholine receptor autoantibodies.[29] A small study of adult patients found elevated α1, β1 and β2 adrenergic receptor autoantibodies.[30] A small randomized crossover design trial found that patients with postural orthostatic tachychardia improved with Mestinon.[31]

Increasing and decreasing acetylcholine[edit | edit source]

Many classes of drugs including benzodiazepines, opiods, anesthetics, and some antihistimanes such as Benadryl are anticholinergic.[citation needed] During exercise, levels of acetylcholine drop.[32]

Acetylcholinesterase inhibitors[edit | edit source]

Acetylcholinesterase is an enzyme that breaks down acetylcholine. Acetylcholinesterase inhibitors block or downregulate the activity of acetylcholinesterase; in turn, because there is less enzyme breaking down acetylcholine, the amount of circulating acetylcholine increases.

The following compounds are acetylcholinesterase inhibitors:

  • pyridostigmine (Mestinon) - A peripheral AChE inhibitor, pyridostigmine is unable to cross the blood brain barrier due to its chemical structure. [33]
  • huperzine A (crosses blood-brain barrier)[citation needed]
  • galantamine - A central/peripheral AChE inhibitor. While prescription only in some countries, galantamine is available over the counter in the United States.
  • blueberries[34]

Research studies related to ME/CFS[edit | edit source]

  • 2004, Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome[35] - (Abstract)

See also[edit | edit source]

Learn more[edit | edit source]

References[edit | edit source]

  1. ↑ Molnar, Charles; Gair, Jane (June 13, 2019). [ttps://opentextbc.ca/biology/chapter/19-4-muscle-contraction-and-locomotion/ Concepts of Biology – 1st Canadian Edition]. 1 (1 ed.). B.C. Open Textbook Collection. pp. Chapter 19.4. Retrieved May 28, 2020.
  2. ↑ Čolović, Mirjana B; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M (May 2013). "Acetylcholinesterase Inhibitors: Pharmacology and Toxicology". Current Neuropharmacology. 11 (3): 315–335. doi:10.2174/1570159X11311030006. ISSN 1570-159X. PMC 3648782. PMID 24179466.
  3. ↑ "Direct Route From The Brain To The Immune System Discovered". ScienceDaily. Retrieved August 10, 2018.
  4. ↑ "Scientists uncover new role for neurotransmitter that helps fight infection | Imperial News | Imperial College London". Imperial News. Retrieved August 10, 2018.
  5. ↑ Darby, Matthew; Schnoeller, Corinna; Vira, Alykhan; Culley, Fiona; Bobat, Saeeda; Logan, Erin; Kirstein, Frank; Wess, Jürgen; Cunningham, Adam F. (January 28, 2015). "The M3 Muscarinic Receptor Is Required for Optimal Adaptive Immunity to Helminth and Bacterial Infection". PLOS Pathogens. 11 (1): e1004636. doi:10.1371/journal.ppat.1004636. ISSN 1553-7374. PMID 25629518.
  6. ↑ Darby, Matthew; Schnoeller, Corinna; Vira, Alykhan; Culley, Fiona; Bobat, Saeeda; Logan, Erin; Kirstein, Frank; Wess, Jürgen; Cunningham, Adam F. (January 28, 2015). "The M3 Muscarinic Receptor Is Required for Optimal Adaptive Immunity to Helminth and Bacterial Infection". PLOS Pathogens. 11 (1): e1004636. doi:10.1371/journal.ppat.1004636. ISSN 1553-7374. PMID 25629518.
  7. ↑ Darby, Matthew; Schnoeller, Corinna; Vira, Alykhan; Culley, Fiona; Bobat, Saeeda; Logan, Erin; Kirstein, Frank; Wess, Jürgen; Cunningham, Adam F. (January 28, 2015). "The M3 Muscarinic Receptor Is Required for Optimal Adaptive Immunity to Helminth and Bacterial Infection". PLOS Pathogens. 11 (1): e1004636. doi:10.1371/journal.ppat.1004636. ISSN 1553-7374. PMID 25629518.
  8. ↑ Razani-Boroujerdi, Seddigheh; Behl, Muskaan; Hahn, Fletcher F.; Pena-Philippides, Juan Carlos; Hutt, Julie; Sopori, Mohan L. (February 2008). "Role of muscarinic receptors in the regulation of immune and inflammatory responses". Journal of neuroimmunology. 194 (1–2): 83–88. doi:10.1016/j.jneuroim.2007.11.019. ISSN 0165-5728. PMID 18190972.
  9. ↑ "Acetylcholine via Muscarinic Receptors Inhibits Histamine Release from Human Isolated Bronchi". American Journal of Respiratory and Critical Care Medicine. doi:10.1164/ajrccm.156.2.96-12079#.v7vo-zmrlmv.
  10. ↑ https://www.myknowtions.com/portfolio/autonomic-nervous-alterations-and-mast-cell-degranulation-in-the-exacerbation-of-ulcerative-colitis
  11. ↑ Angelini, Lucia; Bardare, Maria; Martini, Alberto (2002). Immune-mediated Disorders of the Central Nervous System in Children.
  12. ↑ Gebhardt, B.M. (June 26, 2000). "Evidence for antigenic cross-reactivity between herpesvirus and the acetylcholine receptor". Journal of Neuroimmunology. 105 (2): 145–153. ISSN 0165-5728. PMID 10742556.
  13. ↑ Brenner, T.; Timore, Y.; Wirguin, I.; Abramsky, O.; Steinitz, M. (October 1989). "In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated B-lymphocytes derived from patients with myasthenia gravis". Journal of Neuroimmunology. 24 (3): 217–222. ISSN 0165-5728. PMID 2553772.
  14. ↑ Kaminski, Henry J.; Janos, Minarovits. "Epstein-barr virus: Trigger for autoimmunity?". Annals of Neurology. ISSN 0364-5134.
  15. ↑ "Official Brain & Life Home Page". journals.lww.com. Retrieved August 10, 2018.
  16. ↑ http://www.omicsonline.org/open-access/autoantibodies-against-muscarinic-acetylcholine-receptor-on-exocrine-glands-in-sjgren-syndrome-2161-1122.1000265.pdf
  17. ↑ Chaudhuri, A.; Majeed, T.; Dinan, T.; Behan, P.O. (January 1997). "Chronic Fatigue Syndrome: A Disorder of Central Cholinergic Transmission". Journal of Chronic Fatigue Syndrome. 3 (1): 3–16. doi:10.1300/J092v03n01_02. ISSN 1057-3321.
  18. ↑ Tanaka, Susumu; Kuratsune, Hirohiko; Hidaka, Yoh; Hakariya, Yukiko; Tatsumi, Ke-Ita; Takano, Toru; Kanakura, Yuzuru; Amino, Nobuyuki (August 1, 2003). "Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome". International Journal of Molecular Medicine. doi:10.3892/ijmm.12.2.225. ISSN 1107-3756.
  19. ↑ Loebel, Madlen; Grabowski, Patricia; Heidecke, Harald; Bauer, Sandra; Hanitsch, Leif G.; Wittke, Kirsten; Meisel, Christian; Reinke, Petra; Volk, Hans-Dieter (February 2016). "Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome". Brain, Behavior, and Immunity. 52: 32–39. doi:10.1016/j.bbi.2015.09.013. ISSN 1090-2139. PMID 26399744.
  20. ↑ "Autoantibodies found in subset of CFS patients | #MEAction". The MEAction Network. Retrieved August 10, 2018.
  21. ↑ Marshall-Gradisnik, Sonya; Smith, Peter; Nilius, Bernd; Staines, Donald R. (January 1, 2015). "Examination of Single Nucleotide Polymorphisms in Acetylcholine Receptors in Chronic Fatigue Syndrome Patients". Immunology and Immunogenetics Insights. 7: III.S25105. doi:10.4137/III.S25105. ISSN 1178-6345.
  22. ↑ Kawamura, Yasuo; Kihara, Mikihiro; Nishimoto, Kazuhiro; Taki, Mayumi (May 2003). "Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports". Pathophysiology. 9 (3): 189–194. doi:10.1016/S0928-4680(03)00007-5.
  23. ↑ Snorrason, Ernir; Geirsson, Arni; Stefansson, Kari (January 1996). "Trial of a Selective Acetylcholinesterase Inhibitor, Galanthamine Hydrobromide, in the Treatment of Chronic Fatigue Syndrome". Journal of Chronic Fatigue Syndrome. 2 (2–3): 35–54. doi:10.1300/J092v02n02_04. ISSN 1057-3321.
  24. ↑ Berwaerts, J.; Moorkens, G.; Abs, R. (April 1998). "Secretion of growth hormone in patients with chronic fatigue syndrome". Growth Hormone & IGF Research. 8: 127–129. doi:10.1016/S1096-6374(98)80036-1.
  25. ↑ Moorkens, G.; Wynants, H.; Abs, R. (April 1998). "Effect of growth hormone treatment in patients with chronic fatigue syndrome: A preliminary study". Growth Hormone & IGF Research. 8: 131–133. doi:10.1016/S1096-6374(98)80037-3.
  26. ↑ Johansson, Madeleine; Ricci, Fabrizio; Schulte, Janin; Persson, Margaretha; Melander, Olle; Sutton, Richard; Hamrefors, Viktor; Fedorowski, Artur (April 21, 2021). "Circulating levels of growth hormone in postural orthostatic tachycardia syndrome". Scientific Reports. 11 (1): 8575. doi:10.1038/s41598-021-87983-5. ISSN 2045-2322.
  27. ↑ "A Mestinon Miracle: Vagus Nerve Stimulating Drug Helps Long Time ME/CFS Patient Exercise - Health Rising". Health Rising. June 17, 2016. Retrieved August 10, 2018.
  28. ↑ Oliveira, R.K. (2016). "Pyridostigmine for Exercise Intolerance Treatment in Preload Failure". American Journal of Respiratory and Critical Care Medicine.
  29. ↑ Li, Jiawei; Zhang, Qingyou; Liao, Ying; Zhang, Chunyu; Hao, Hongjun; Du, Junbao (August 3, 2014). "The Value of Acetylcholine Receptor Antibody in Children with Postural Tachycardia Syndrome". Pediatric Cardiology. 36 (1): 165–170. doi:10.1007/s00246-014-0981-8. ISSN 0172-0643.
  30. ↑ Li, Hongliang; Yu, Xichun; Liles, Campbell; Khan, Muneer; Vanderlinde‐Wood, Megan; Galloway, Allison; Zillner, Caitlin; Benbrook, Alexandria; Reim, Sean (January 27, 2014). "Autoimmune Basis for Postural Tachycardia Syndrome". Journal of the American Heart Association. 3 (1). doi:10.1161/jaha.113.000755. ISSN 2047-9980. PMC 3959717. PMID 24572257.
  31. ↑ Raj, S.R. (May 31, 2005). "Acetylcholinesterase Inhibition Improves Tachycardia in Postural Tachycardia Syndrome". Circulation. 111 (21): 2734–2740. doi:10.1161/circulationaha.104.497594. ISSN 0009-7322.
  32. ↑ Conlay, L. A., Sabournjian, L. A., and Wurtman, R. J. Exercise and neuromodulators: choline and acetylcholine in marathon runners.Int. J. Sports Med. 13(Suppl. 1):S141-142, 1992
  33. ↑ Anderson, Tim; Pope, Carey N. (2017). "Pyridostigmine ☆". =J. Med. Chem. Elsevier: B978012801238397627X. doi:10.1016/b978-0-12-801238-3.97627-x. ISBN 978-0-12-801238-3.
  34. ↑ Papandreou, Magdalini A.; Dimakopoulou, Andriana; Linardaki, Zacharoula I.; Cordopatis, Paul; Klimis-Zacas, Dorothy; Margarity, Marigoula; Lamari, Fotini N. (March 17, 2009). "Effect of a polyphenol-rich wild blueberry extract on cognitive performance of mice, brain antioxidant markers and acetylcholinesterase activity". Behavioural Brain Research. 198 (2): 352–358. doi:10.1016/j.bbr.2008.11.013. ISSN 1872-7549. PMID 19056430.
  35. ↑ Spence, V.A; Khan, F; Kennedy, G; Abbot, N.C; Belch, J.J.F (April 2004). "Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome". Prostaglandins, Leukotrienes and Essential Fatty Acids. 70 (4): 403–407. doi:10.1016/j.plefa.2003.12.016.
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