The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation

Laboratory of Biomedical Science, North Shore LIJ-Research Institute, Manhasset, NY 11030, USA.
Molecular Medicine (Impact Factor: 4.51). 05/2003; 9(5-8):125-34.
Source: PubMed


This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.

Download full-text


Available from: Christopher Czura
    • "The activation of these receptors decreases the release of proinflammatory mediators (Gallowitsch-Puerta and Tracey, 2005;Johnston and Webster 2009;Pavlov et al., 2003;Otmishi et al., 2008;Wang et al., 2003). Suppression of pro-inflammatory cytokine release by increased vagal efferent activity has been shown to protect against conditions associated with systemic or pulmonary inflammatory responses (Bencherif et al., 2011;Borovikova et al., 2000;Guarini et al., 2003;Pavlov et al., 2003;van Westerloo et al., 2006). ARDS being an acute inflammatory disorder, it is likely that such vagally mediated mechanisms are involved in the pathophysiology. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mesobuthus tamulus (MBT) venom and oleic acid (OA) have been shown to produce acute respiratory distress syndrome (ARDS) involving different mechanisms. The role of vagally mediated anti-inflammatory pathway in ARDS is poorly understood. Therefore, the effects of vagal efferent stimulation on these two models of ARDS were examined. Experiments were performed on anesthetized adult rats. Parameters like ventilatory changes (respiratory frequency and minute ventilation), hypoxemic status (PaO2/FiO2 ratio; P/F ratio), survival time, pulmonary water content and histopathological evidences of lung injury were determined to assess the severity of ARDS. In addition, heart rate (HR) and mean arterial pressure (MAP) were monitored. Injection of OA/MBT venom produced respiratory alterations, hypoxemia, pulmonary edema and histopathological changes demonstrating the development of ARDS. In both the groups, animals died around 60 min. Tachypnea and hyperventilation were seen after OA while bradypnea and hypoventilation were seen after MBT venom. Pulmonary edema was absent in vagotomised animals in MBT venom group but not in OA group. Further, electrical stimulation of the cut peripheral ends of vagii prolonged the survival time and attenuated all the parameters of MBT venom-induced ARDS significantly. In case of OA, there was improvement in histopathological changes but the survival time of animals was not prolonged. Stimulation of α7-nicotinic receptors (by pretreatment with GTS-21) exacerbated OA as well as MBT venom-induced ARDS. The present results indicate that vagal efferent stimulation protects against MBT venom-induced ARDS.
    No preview · Article · Nov 2015 · Toxicon
  • Source
    • "Based on adult literature, nonpharmacologic strategies have been designed for use in the pediatric patient, but there remains a lack of evidence for pharmacologic treatment when these measures fail (Meagher 2001). Multiple central nervous system pathways have been implicated in the development of delirium , including dopaminergic, serotoninergic, glutaminergic, and cholinergic pathways in the cerebral cortex, striatum, substantia nigra, and thalamus (Pavlov et al. 2003; Gunther et al. 2008). This makes pharmacotherapy with psychoactive agents, particularly quetiapine, a physiologically reasonable choice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Quetiapine is an atypical antipsychotic that has been used off-label for the treatment of intensive care unit (ICU) delirium in the adult population, with studies demonstrating both efficacy and a favorable safety profile. Although there is a potential role for quetiapine in the treatment of pediatric ICU delirium, there has been no systematic reporting to date of safety in this patient population. Methods: Pharmacy records were used to identify 55 consecutive pediatric ICU patients who were diagnosed with delirium and received quetiapine. A comprehensive retrospective medical chart review was performed to collect data on demographics, dosing, and side effects. Results: Fifty patients treated between January 2013 and November 2014 were included, and five patients were excluded from the study. Subjects ranged in age from 2 months to 20 years. Median daily dose was 1.3 mg/kg/day, and median duration of treatment was 12 days. There were three episodes of QTc prolongation that were clinically nonsignificant with no associated dysrhythmia: Two resolved over time without intervention, and one resolved with decrease in quetiapine dosage. There were no episodes of extrapyramidal symptoms or neuroleptic malignant syndrome. Conclusions: In this population of critically ill youth, short-term use of quetiapine as treatment for delirium appears to be safe, without serious adverse events. Further research is required to assess efficacy and evaluate for long-term effects. A prospective, randomized, placebo-controlled study of quetiapine in managing pediatric delirium is necessary.
    Full-text · Article · Oct 2015 · Journal of child and adolescent psychopharmacology
  • Source
    • "The afferent and efferent limbs of the vagus nerve constitute the cholinergic antiinflammatory pathway (Pavlov et al., 2003; Tracey, 2002) which acts as an interface "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose: In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. Experimental approach: Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. Key results: AN917 and AN680 (1-10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 μmol · kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%. Conclusion and implications: Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression.
    Full-text · Article · Oct 2014 · British Journal of Pharmacology
Show more