Effect of the a7nAChR agonist GTS-21 on inflammation during human endotoxemia

Introduction

Activation of the cholinergic anti-inflammatory pathway via vagus nerve stimulation or a7nAChR agonists improves outcome in animal models of endotoxemia, sepsis and experimental arthritis. This vagal anti-inflammatory pathway is mediated by the nicotinergic a7nACh receptor that can be selectively stimulated by GTS-21. Up to now, the anti-inflammatory effects of oral administration of GTS-21 in humans in vivo have not been investigated. The aim of this study was to investigate the anti-inflammatory effects of oral administration of GTS-21 on the inflammatory response in the human endotoxemia model.

Methods

We performed a double-blind placebo-controlled randomized study in 12 healthy, nonsmoking male volunteers (18 to 28 years) during experimental endotoxemia. Subjects received 150 mg GTS-21 or placebo orally three times daily 3 days before lipopolysaccharide (LPS) injection and on the day of the experiment, the last dose 1 hour before LPS administration (t = -1). One hour after the last dose of GTS-21 or placebo, LPS derived from Escherichia coli O:113 was injected (2 ng/kg intravenously).

Results

The main study endpoint was the concentration of circulating cytokines after LPS in the absence and presence of GTS-21. The effects of GTS-21 on TNFα and IL-10 release are shown in Figures 1 and 2. There was a trend towards a decrease in TNFα levels and an increase in IL-10 levels after GTS-21 administration. A similar trend was observed in levels of other proinflammatory and anti-inflammatory cytokines.

Figure 1

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Figure 2

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Conclusion

GTS-21 suppresses TNFα and stimulates IL-10 release during human endotoxemia in healthy human volunteers, resulting in a shift towards a more anti-inflammatory pattern. This effect may have potential for in vivo modulation of the innate immune response.