Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia
Open accessAbstract
TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this “cholinergic antiinflammatory pathway” inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents.
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Intracerebral administration of muscarine agonists stimulates an increase in vagus nerve signaling to the heart as measured by increasing instantaneous heart rate variability.
“Intracerebral administration of muscarine agonists also stimulates an increase in vagus nerve signaling to the heart as measured by increasing instantaneous heart rate variability”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [34]
Intracerebroventricular administration of muscarine receptor agonists significantly decreases serum TNF levels during endotoxemia.
“Recent results showing that intracerebroventricular administration of muscarine receptor agonists significantly decreases serum TNF levels during endotoxemia indicate that muscarinic brain networks also regulate the cytokine-controlling function of the vagus nerve.(34).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [34]
Centrally acting cholinergic agonists used in the treatment of Alzheimer disease can modulate peripheral immune responses by stimulating brain networks to activate the cholinergic antiinflammatory pathway.
“Our recent evidence indicates that centrally acting cholinergic agonists used in the treatment of Alzheimer disease can modulate peripheral immune responses by stimulating brain networks to activate the cholinergic antiinflammatory pathway (34).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [34]
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- Authors
- Pavlov, V. A., Ochani, M., Gallowitsch-Puerta, M., Ochani, K., Huston, J. M., Czura, C. J., Al-Abed, Y., & Tracey, K. J.
- Affiliations
- Laboratories of *Biomedical Science and
- Medicinal Chemistry,
- Feinstein Institute for Medical Research (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-03-20
- Volume
- 103
- Issue
- 13
- Pages
- 5219-5223
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1405626
- OpenAlex
- W1979952002
- Cited by
- 336
- References
- 37
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 11 · 2023: 9 · 2022: 14 · 2021: 19 · 2020: 17 · 2019: 14 · 2018: 16 · 2017: 15 · 2016: 15 · 2015: 16 · 2014: 19 · 2013: 23 · 2012: 21
- FWCI
- 15.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM089807)
- National Center for Research Resources (M01RR018535)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- muscarinic receptors, cholinergic anti-inflammatory pathway, endotoxemia, systemic inflammatory response, TNF-α, vagus nerve, methoctramine, McN-A-343, muscarine, heart rate variability, sepsis, anti-inflammatory agents, central nervous system
- MeSH terms
- Animals, Brain, Diamines, Heart Rate, Inflammation, Male, Receptors, Muscarinic, Tumor Necrosis Factor-alpha, Muscarinic Agonists, Systemic Inflammatory Response Syndrome, Endotoxemia, Rats
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