In vivo effects of the selective a7nAChR agonist GTS-21 on inflammation

The innate immune response is the first line of defense against invading
pathogens. This tightly regulated system consists of a wide variety of
chemokines, cytokines, cell associated receptors and other mediators
orchestrating the initial response to infection. Experimental evidence in the
past several years has demonstrated that activation of the efferent vagus nerve
has an inhibitory effect on the innate immune response (the cholinergic
anti-inflammatory pathway). Several in vitro studies have demonstrated that
pretreatment of cultured human macrophages with the principal vagal
neurotransmitter acetylcholine, significantly attenuates the LPS-induced
release of pro-inflammatory mediators such as TNF-a, IL-6, IL-1b, IL-18 and
HMGB1, while release of the anti-inflammatory cytokine IL-10 was unaffected.
Moreover, vagal nerve electrical stimulation attenuates serum TNF-a and IL-6
levels in animals after endotoxin administration and prevents the development
of shock. In contrast, vagotomized animals exhibited elevated levels of
pro-inflammatory cytokines with aggravation of shock.
The anti-inflammatory effect of the vagal nerve is mediated by the a7 nicotinic
acetylcholine receptor (a7nAChR) expressed on macrophages and other
cytokine-producing cells. GTS-21 (E-3-(2,4)-dimethoxybenzylidene anabaseine) is
a highly specific a7nAchR agonist, that has been developed for the treatment of
Alzheimer*s disease that has been studied in a few inflammation-related models.
Stimulation of the α7nAChR by GTS-21 in animal models of inflammation resulted
in a profound anti-inflammatory shift of the pro-/anti-inflammatory balance.
So far, no data are available on the anti-inflammatory effects of GTS-21 in
humans in vivo.

Aim of this study is to investigate the effects of oral administration of
GTS-21 in healthy volunteers on cytokine release in ex-vivo TLR agonists
stimulated whole blood .

Pharmacokinetic and pharmacodynamic data will be collected with respect to the
anti-inflammatory effects of GTS-21 and its effects on the expression of TLR2,
TLR4 and α7nAChR.

Interventional study

Oral administration of GTS-21

Oral GTS-21: Until date, 87 healthy male volunteers were enrolled in four Phase
I studies that assessed the safety, tolerability, pharmacokinetics, and effects
on cognitive function of oral administration of GTS-21 of which 77 subjects
received GTS-21 and 10 subjects received placebo. GTS-21 was found to be well
tolerated both up to a single dose of 250 mg/day, as well as up to a dose of
150 mg three times daily (450 mg/day) in healthy male subjects. The most common
adverse event was headache, which occurred in 27% of subjects in the GTS-21
group compared to 21% of subjects in the placebo group. There were no serious
adverse events, or severe adverse events reported during these studies. In one
patient in the GTS-21 group transient mild elevation of liver enzymes was
detected, without signs of hepatic dysfunction.
GTS-21 is currently being studied in a Phase II clinical trial assessing safety
and cognitive improvement in patients with ADHD.

1 periferal intra-venous line: after removal ligth pressure to avoid hematoma.

Total blood withdrawal: approximately 350 ml.