Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway

Bernik, Thomas R.; Friedman, Steven G.; Ochani, Mahendar; DiRaimo, Robert; Ulloa, Luis; Yang, Huan; Sudan, S.; Czura, Christopher J.; Ivanova, Svetlana; Tracey, Kevin J.

doi:10.1084/jem.20011714

Cited by 472 publications

(358 citation statements)

References 30 publications

(35 reference statements)

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“…CVC can be improved via biofeedback (e.g., Nolan et al, 2005), leading to a reduction of depressive symptoms (Siepmann, Aykac, Unterdorfer, Petrowski, & Mueck-Weymann, 2008). CVC can also be enhanced by pharmacological and surgical means (Bernik et al, 2002; Singh, Kandala, & Camm, 2014). Interestingly, Tsai, Kuo, Lee, and Yang (2015) showed that slow-paced breathing (at a frequency of 0.1 Hz) can lead to increases in CVC as well, which improved sleep quality among individuals with insomnia.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Vagal Control and Depressive Symptoms: The Moderating Role of Sleep Quality

Werner

Ford

Mauss

et al. 2016

Behavioral Sleep Medicine

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Lower cardiac vagal control (CVC) has been linked to greater depression. However, this link has not been consistently demonstrated, suggesting the presence of key moderators. Sleep plausibly is one such factor. Therefore, we investigated whether sleep quality moderates the link between CVC (quantified by high-frequency heart rate variability, HF-HRV) and depressive symptoms (assessed using established questionnaires) in 29 healthy women. Results revealed a significant interaction between HF-HRV and sleep quality in predicting depressive symptoms: participants with lower HF-HRV reported elevated depressive symptoms only when sleep quality was also low. In contrast, HF-HRV was not associated with depressive symptoms when sleep quality was high, suggesting a protective function of high sleep quality in the context of lower CVC.

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Section: Discussionmentioning

confidence: 99%

Cardiac Vagal Control and Depressive Symptoms: The Moderating Role of Sleep Quality

Werner

Ford

Mauss

et al. 2016

Behavioral Sleep Medicine

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“…Injections. Rats were anesthetized and placed in a stereotaxic head frame (Stoelting) as described (6). The incisor bar was adjusted until the plane defined by the lambda and bregma was parallel to the base plate.…”

Section: Methodsmentioning

confidence: 99%

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Pavlov

Ochani

Gallowitsch-Puerta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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296

215

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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. muscarinic receptors ͉ systemic inflammation ͉ TNF ͉ vagus nerve T he overproduction of cytokines, including TNF, mediates tissue damage during the response to injury or pathogenic invasion (1). Physiological and molecular mechanisms that control TNF production maintain cytokine homeostasis and minimize or prevent damage during the host response to infection, injury, arthritis, and other disorders (1-3). Recently, we found (4-6) that electrical or pharmacological activation of the efferent vagus nerve inhibits the release of TNF and attenuates the development of endotoxin-induced shock in rodents. Stimulation of the efferent vagus nerve activates the release of acetylcholine. Although the vagus nerve is a ''classical'' cholinergic regulator of visceral functions in which peripheral muscarinic acetylcholine receptors have a major mediating role, the vagusnerve cytokine-inhibiting activity (which is termed ''the cholinergic antiinflammatory pathway'') requires signaling through nicotinic ␣ 7 subunit-containing receptors (4, 5).Studies have implicated muscarinic receptor-dependent mechanisms in the central modulation and integration of vagal regulation of visceral functions. For example, vagus nerve control of glycogen synthesis in the liver, the Bezold-Jarish cardiovascular reflex and the regulation of exocrine pancreatic secretion are modulated centrally by brain muscarinic receptor mechanisms (7-10). Thus, we reasoned that brain muscarinic receptors could be involved in the central regulation of the vagus-nerve immunomodulatory function. Our results indicate that central cholinergic activation by selective muscarinic receptor ligands significantly inhibits systemic TNF in endotoxemic rats and activates th...

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“…Activation of this anti-inflammatory pathway can be achieved by the following: 1) direct stimulation of the vagus nerve [16,17] , 2) the use of nicotine or nicotinic agonists (GTS-21, CAP55) to activate the α7nAChR [18][19][20] , and 3) the use of cholinesterase inhibitors (physostigmine, galantamine) [21][22][23] .…”

Section: Discussionmentioning

confidence: 99%

Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors

Sun

Zhang

et al. 2012

Acta Pharmacol Sin

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Aim: To evaluate the anti-effects of anisodamine and neostigmine in animal models of endotoxic and hemorrhagic shock. Methods: Kunming mice were injected with lipopolysaccharide (LPS 30 mg/kg, ip) to induce endotoxic shock. Anisodamine (12.5, 25, and 50 mg/kg, ip) and neostigmine (12.5, 25, and 50 μg/kg, ip) were administered immediately after LPS injection. Survival rate was monitored, and the serum levels of TNF-α and IL-1β were analyzed using ELISA assays. The effects of anisodamine and neostigmine were also examined in α7 nicotinic acetylcholine receptor (α7 nAChR) knockout mice with endotoxic shock and in Beagle dogs with hemorrhagic shock. Results: In mice with experimental endotoxemia, combined administration of anisodamine and neostigmine significantly increased the survival rate and decreased the serum levels of inflammatory cytokines, as compared to those produced by either drug alone. The antishock effect of combined anisodamine and neostigmine was abolished in α7 nAChR knockout mice. On the other hand, intravenous injection of the combined anisodamine and neostigmine, or the selective α7 nAChR agonist PNU282987 exerted similar anti-shock effects in dogs with hemorrhagic shock. Conclusion:The results demonstrate that combined administration of anisodamine and neostigmine produces significant anti-shock effects, which involves activation of α7 nAChRs.

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Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway

Cited by 472 publications

References 30 publications

Cardiac Vagal Control and Depressive Symptoms: The Moderating Role of Sleep Quality

Cardiac Vagal Control and Depressive Symptoms: The Moderating Role of Sleep Quality

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors

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