Effects of the α7 nicotinic acetylcholine receptor agonist GTS-21 on the innate immune response in humans

• Published in: Shock (Augusta, Ga.) Vol. 36; no. 1; p. 5
• Main Authors: Kox, Matthijs, Pompe, Jan C, Gordinou de Gouberville, Marije C, van der Hoeven, Johannes G, Hoedemaekers, Cornelia W, Pickkers, Peter
• Format: Journal Article
• Language: English
• Published: United States 01.07.2011
• Subjects: Adolescent; Adult; alpha7 Nicotinic Acetylcholine Receptor; Anti-Inflammatory Agents - blood; Anti-Inflammatory Agents - pharmacology; Benzylidene Compounds - blood; Benzylidene Compounds - pharmacology; Endotoxemia - blood; Endotoxemia - chemically induced; Endotoxemia - immunology; Hemodynamics - drug effects; Humans; Immunity, Innate - drug effects; Interleukin 1 Receptor Antagonist Protein - blood; Interleukin-10 - blood; Interleukin-6 - blood; Lipopolysaccharides - toxicity; Male; Nicotinic Agonists - blood; Nicotinic Agonists - pharmacology; Pyridines - blood; Pyridines - pharmacology; Receptors, Nicotinic - metabolism; Tumor Necrosis Factor-alpha - blood; Young Adult
• ISSN: 1540-0514
• DOI: 10.1097/shk.0b013e3182168d56

The vagus nerve can reflexively attenuate the innate immune response via binding of the vagal neurotransmitter acetylcholine (ACh) to the α7 nicotinic ACh receptor (α7nAChR). We recently reported potent anti-inflammatory effects of the α7nAChR agonist GTS-21 in human leukocytes. In the present work, we investigated the anti-inflammatory effects of GTS-21 on the innate immune response during experimental human endotoxemia. We performed a double-blind placebo-controlled pilot study in 14 healthy nonsmoking male volunteers. Subjects received 150 mg GTS-21 (n = 7) or placebo (n = 7) orally three times per day during 3 days before endotoxin administration and on the day of the human endotoxemia experiment. This GTS-21 dosage scheme is the highest reported to be safe in humans. Subsequently, subjects were i.v. administered 2 ng/kg endotoxin (LPS derived from Escherichia coli O:113). Serial blood withdrawals were performed to determine GTS-21 plasma concentrations and inflammatory mediators. Plasma concentrations of GTS-21 and its active metabolite 4-OH-GTS-21 were highly variable between subjects. LPS administration resulted in a transient inflammatory response. There were no differences in the LPS-induced cytokine response between the GTS-21- and placebo-treated groups. However, within the GTS-21-treated group, higher GTS-21 plasma concentrations correlated with lower levels of TNF-α (r = -0.78, P = 0.03), IL-6 (r = -0.76, P = 0.04), and IL-1RA (r = -0.86, P = 0.01), but not IL-10 (r = -0.35, P = 0.25). In conclusion, although higher GTS-21 plasma concentrations significantly correlated with lower cytokine levels, the highest dose tested to be safe in humans did not result in significant differences in inflammatory mediators between the GTS-21- and placebo-treated groups.