Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis*

Pavlov, Valentin A.; Ochani, Mahendar; Yang, Lihong; Gallowitsch-Puerta, Margot; Ochani, Kanta; Lin, Xinchun; Levi, Jelena; Parrish, William R.; Rosas-Ballina, Mauricio; Czura, Christopher J.; LaRosa, Gregory J.; Miller, Edmund J.; Tracey, Kevin J.; Al‐Abed, Yousef

doi:10.1097/01.ccm.0000259381.56526.96

Cited by 331 publications

(283 citation statements)

References 27 publications

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“…Acetylcholine can bind to different receptors and play different physiological roles (Paleari et al, 2008). After binding to the α7 nicotinic acetylcholine receptor, acetylcholine can inhibit the inflammatory mediators (i.e., the so-called 'cholinergic anti-inflammatory pathway') (Wang et al, 2003) and have an antiinflammatory effect via activation of the cholinergic system (Libert, 2003;Pavlov and Tracey, 2004;Pavlov et al, 2007). ChE is an important part of the cholinergic system since it is a hydrolase that is upstream of the neurotransmitter (Rodriguez et al, 2002;Paraoanu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes of serum cholinesterase activity after severe trauma

Qian

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:Objective: The aim of the present study was to examine dynamic changes in serum cholinesterase (ChE) activity during early-stage severe trauma and the clinical significance of these changes. Methods: This prospective, observational study included 81 patients with severe trauma who were treated between October 2011 and April 2013 in the emergency intensive care unit (EICU) of a university-affiliated, tertiary-care, grade A general hospital in China. Serum ChE activity was measured on Days 1, 3, and 7 post-injury. The correlation of dynamic changes in serum ChE activity with trauma severity and prognosis was assessed. Correlations between changes in serum ChE activity after injury and albumin (ALB), prealbumin (PAB), transferrin (TRF), and C-reactive protein (CRP) levels were also analyzed. Results: Serum ChE activity in trauma patients was 42.3%-50.2% lower on Days 1, 3, and 7 compared with the control (P<0.001 for all time points), and it continued to decrease after Day 7 in both the survival and death subgroups. In the subgroup with an injury severity score (ISS) of ≤25, serum ChE activity initially decreased, but eventually increased. However, activity decreased continuously in the ISS>25 subgroup. ChE activity was significantly lower in both the death and the ISS>25 subgroups than in the survival and ISS≤25 subgroups on Days 1, 3, and 7 after injury. Activity was negatively correlated with ISS and acute physiology and chronic health evaluation III (APACHE III) at all time points. When comparing the receiver operating characteristic (ROC) curves for predicting prognosis, the area under the curve (AUC) in the plot of serum ChE was similar to the AUCs in plots of ISS and APACHE III, but significantly smaller than the AUC in the plot of the trauma and injury severity score (TRISS). Serum ChE activity was positively correlated with ALB, PAB, and TRF at all time points post-injury. Activity was not significantly correlated with CRP on Day 1, but was significantly and negatively correlated with CRP on Days 3 and 7. Conclusions: There is a significant decrease in serum ChE activity after severe trauma. Serum ChE may be regarded as a negative acute phase protein (APP) and the dynamic changes in serum ChE may be useful as an auxiliary indicator for evaluating trauma severity and predicting prognosis.

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Section: Discussionmentioning

confidence: 99%

Dynamic changes of serum cholinesterase activity after severe trauma

Qian

et al. 2014

J. Zhejiang Univ. Sci. B

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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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“…Activation of this pathway by stimulation of the vagus nerve suppresses serum TNF levels in endotoxemic animals (3,4), but fails to cause statistically significant effects in mice lacking the α7nAChR (4). Accordingly, α7nAChR agonists, including GTS-21, reduce systemic proinflammatory cytokine levels during murine endotoxemia, sepsis (9), and other inflammatory conditions (10,11), and improve survival (9).…”

Section: Introductionmentioning

confidence: 99%

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

Parrish

Rosas-Ballina

Gallowitsch-Puerta

et al. 2008

Mol Med

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292

205

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The α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural α7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the α7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1-50 mM) dosedependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-κB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in α7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from α7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires α7nAChR-mediated signaling.

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Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis*

Abstract: These findings are of interest for the development of alpha7-nicotinic acetylcholine receptor agonists as a new class of anti-inflammatory therapeutics.

Cited by 331 publications

References 27 publications

Dynamic changes of serum cholinesterase activity after severe trauma

Dynamic changes of serum cholinesterase activity after severe trauma

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

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

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