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Published on: April 11, 2012
The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in
Anne J van der Meer1, Brendon P Scicluna, Perry D Moerland
11Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands. 2Bioinformatics Laboratory, Department of Clinical Epidemiology, Academic Medical Center, Amsterdam, The Netherlands. 3GlaxoSmithKline, Durham, North Carolina. 4Sirtris, A GSK Company, Cambridge, MA.
Objectives:
Sirtuin 1 influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin 1 activator, SRT2104, on inflammation and coagulation induced by lipopolysaccharide in humans.
Design:
A randomized, double-blind, placebo-controlled study.
Setting:
An academic hospital.
Subjects:
Twenty-four healthy humans.
Interventions:
All subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups (n=8 per group): 1) pretreatment with oral SRT2104 for 7 days (2 g/d), 2) pretreatment with a single SRT2104 dose (2 g), or 3) placebo.
Measurements And Main Results:
SRT2104 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [p<0.05] and 80.9% [p=0.078] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [p<0.05 vs placebo] and 77.1% [p<0.05 vs placebo] after single and repeated SRT2104 ingestion, respectively, while not affecting tumor necrosis factor-α and interleukin-10 release). SRT2104 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2104 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F1+2 (mean peak levels 57.9% [p<0.05] and 64.2% [p<0.05] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2104.
Conclusions:
This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule.
Insights
SRT2104, a sirtuin 1 activator, reduced inflammation and coagulation in humans following lipopolysaccharide challenge. This study demonstrates the first human evidence of biological anti-inflammatory and anticoagulant effects from a small molecule activator of sirtuin 1.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Sirtuin 1 (SIRT1) is a key regulator of cellular functions, including gene expression, through protein deacetylation.
- Small molecule activators of SIRT1 are being investigated for therapeutic potential.
Purpose of the Study:
- To evaluate the effects of the SIRT1 activator SRT2104 on lipopolysaccharide (LPS)-induced inflammation and coagulation in healthy humans.
- To determine if SRT2104 exhibits anti-inflammatory and anticoagulant properties in a human model.
Main Methods:
- A randomized, double-blind, placebo-controlled study was conducted in an academic hospital.
- Twenty-four healthy subjects received an intravenous LPS injection and were randomized to receive oral SRT2104 (7 days), a single SRT2104 dose, or placebo.
- Key inflammatory markers (cytokines, C-reactive protein) and coagulation markers (F1+2, vWF, t-PA, PAI-1) were measured.
Main Results:
- SRT2104 significantly attenuated LPS-induced release of interleukin-6 and interleukin-8, but not TNF-α or IL-10.
- The acute phase protein response, indicated by C-reactive protein, was reduced by SRT2104.
- SRT2104 inhibited coagulation activation, evidenced by lower plasma levels of prothrombin fragment F1+2.
- Endothelial activation and fibrinolysis markers were not significantly affected by SRT2104.
Conclusions:
- This study provides the first human data demonstrating that SRT2104, a small molecule SIRT1 activator, possesses biological anti-inflammatory and anticoagulant effects.
- These findings support the potential therapeutic role of SIRT1 activation in inflammatory and thrombotic conditions.
