Efferent Vagal Fibre Stimulation Blunts Nuclear Factor-κB Activation and Protects Against Hypovolemic Hemorrhagic Shock

Guarini, Salvatore; Altavilla, Domenica; Cainazzo, Maria-Michela; Giuliani, Daniela; Bigiani, Albertino; Marini, Herbert; Squadrito, Giovanni; Minutoli, Letteria; Bertolini, Alfio; Marini, Rolando; Adamo, Elena Bianca; Venuti, Francesco S.; Squadrito, Francesco

doi:10.1161/01.cir.0000050627.90734.ed

Cited by 297 publications

(249 citation statements)

References 21 publications

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“…This indicates that the recently identified vagus nervemediated cholinergic antiinflammatory pathway (Borovikova et al, 2000;Guarini et al, 2003;Altavilla et al, 2006;Tracey, 2007) is involved in the neuroprotective effect of melanocortins against ischemic stroke, as it occurs in circulatory shock and myocardial ischemia (Guarini et al, 2004;Mioni et al, 2005).…”

Section: Discussionmentioning

confidence: 93%

Retracted: Vagus Nerve Mediates the Protective Effects of Melanocortins against Cerebral and Systemic Damage after Ischemic Stroke

Ottani

Giuliani

Mioni

et al. 2008

J Cereb Blood Flow Metab

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A vagus nerve-mediated, efferent cholinergic protective pathway activated by melanocortins is operative in circulatory shock and myocardial ischemia. Moreover, melanocortins have neuroprotective effects against brain damage after ischemic stroke. Here we investigated cerebral and systemic pathophysiologic reactions to focal cerebral ischemia in rats induced by intrastriatal microinjection of endothelin-1, and the possible protective role of the melanocortin-activated vagal cholinergic pathway. In the striatum and liver of saline-treated control rats, the activation of extracellular signal-regulated kinases, c-jun N-terminal kinases, and caspase-3, the increase in tumor necrosis factor-a (TNF-a) concentration and DNA fragmentation, as well as the increase in TNF-a plasma levels, occurred 10 and 20 h after the ischemic insult suggesting an activation of inflammatory and apoptotic responses. Treatment with [Nle 4 , D-Phe 7 ]a-melanocyte-stimulating hormone (NDP-a-MSH; 3 or 9 h after stroke) suppressed the inflammatory and apoptotic cascades at central and peripheral level. Bilateral vagotomy and pharmacologic blockade of peripheral nicotinic acetylcholine receptors blunted the protective effect of NDP-a-MSH. The present results show that focal brain ischemia in rats causes significant effects not only in the brain, but also in the liver. Moreover, our data support the hypothesis that a protective, melanocortin-activated, vagal cholinergic pathway is likely operative in conditions of ischemic stroke.

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Section: Discussionmentioning

confidence: 93%

Retracted: Vagus Nerve Mediates the Protective Effects of Melanocortins against Cerebral and Systemic Damage after Ischemic Stroke

Ottani

Giuliani

Mioni

et al. 2008

J Cereb Blood Flow Metab

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“…10,14 The a7nAChR can be considered to be a peripheral 'immune' component of the cholinergic anti-inflammatory pathway. 18,19 Molecular mechanisms supporting these anti-inflammatory effects include nuclear factor kappa B pathway inhibition, 20 activation of Janus activated kinase --signal transducer and activator of transcription 21 and the consequent inhibition of TNFa production. 22 A functional role of nicotinic acetylcholine receptors (nAChRs) has already been demonstrated in rat adipocytes.…”

Section: Discussionmentioning

confidence: 99%

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

et al. 2012

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BACKGROUND: It is known that cholinergic anti-inflammatory reflex regulates inflammation in peripheral tissues. Nicotinic acetylcholine receptors (nAChRs) are mediators of this anti-inflammatory pathway and also non-neuronal cells express functional nAChrs. A role for a7-subtype acetylcholine cholinergic receptor (a7nAChR) in insulin sensitivity improvement has already been shown in rodents both in vivo and in vitro. However, no data are available on a7nAChR expression in human adipocytes. OBJECTIVE: To investigate the expression and protein content of a7nAChR in human subcutaneous adipose tissue (SAT) and in isolated mature adipocytes. DESIGN: A total of 39 SAT biopsy specimens obtained from obese and normal-weight subjects were used to assess a7nAChR messenger RNA levels and to stimulate a7nAChR with a specific agonist and antagonist in vitro. Additional SATs from eight non-diabetic obese subjects were also studied, before and after a 3-month lifestyle intervention. RESULTS: a7nAChR expression was significantly lower in the SAT of obese subjects compared with that of normal-weight subjects. In mature adipocytes isolated from morbidly obese subjects (body mass index440 kg m À2 ), a7nAChR expression was 75% lower compared with adipocytes from normal-weight subjects. In adipocytes of obese subjects, a7nAChR was downregulated also at protein level. In eight non-diabetic obese subjects, a lifestyle intervention (3 months of diet and physical activity) induced a significant weight loss and an increase in a7nAChR SAT expression. In vitro stimulation of adipocytes with the specific a7nAChR agonist PNU282987 induced a significant anti-inflammatory effect. Furthermore, a similar downregulation of the inflammatory profile, associated with a significant increase in a7nAChR protein level, was observed after genistein stimulation. CONCLUSIONS: These results provide evidence that a7nAChR expression levels are significantly decreased in obese subjects, and that this receptor modulates inflammatory gene expression in human adipocytes. The upregulation of a7nAChR by genistein stimulation opens new insights for the management of low-grade inflammation linked to human obesity.

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“…Inflammatory cytokines plays an important role in acute hypovolemic hemorrhagic shock because anti-TNF-α monoclonal antibodies could increase survival, improve hypotension, and attenuate impairment in vascular reactivity [32] . Recent studies have demonstrated that electrical stimulation of efferent vagal fibers could rapidly reverse hypotension, counteract hepatic NF-κB activation, reduce TNF-α plasma levels and improve survival rate in experimental hemorrhagic shock rats [13,33] . Systemic administration of an acetylcholinesterase inhibitor also improves outcomes after hemorrhagic shock [22] .…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that activation of the α7nAChR-dependent cholinergic anti-inflammatory pathway can control the production of proinflammatory cytokines in experimental models of endotoxic shock and hemorrhagic shock [12,13] . Our previous studies have shown that anisodamine blocks muscarinic receptors and promotes increased endogenous acetylcholine binding to the α7nAChR [6] .…”

Section: Introductionmentioning

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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Efferent Vagal Fibre Stimulation Blunts Nuclear Factor-κB Activation and Protects Against Hypovolemic Hemorrhagic Shock

Cited by 297 publications

References 21 publications

Retracted: Vagus Nerve Mediates the Protective Effects of Melanocortins against Cerebral and Systemic Damage after Ischemic Stroke

Retracted: Vagus Nerve Mediates the Protective Effects of Melanocortins against Cerebral and Systemic Damage after Ischemic Stroke

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

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

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