Agmatine Protects Against the Progression of Sepsis Through the Imidazoline I2 Receptor-Ribosomal S6 Kinase 2-Nuclear Factor-κB Signaling Pathway

Crit Care Med. 2020 Jan;48(1):e40-e47. doi: 10.1097/CCM.0000000000004065.


Objectives: The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis.

Design: Clinical/laboratory investigations.

Setting: Medical centers/University-based research laboratory.

Subjects: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g.

Interventions: Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation.

Measurements and main results: Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα.

Conclusions: Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agmatine / pharmacology
  • Agmatine / therapeutic use*
  • Animals
  • Cells, Cultured
  • Disease Progression
  • Humans
  • Imidazoline Receptors / drug effects
  • Imidazoline Receptors / physiology*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / physiology
  • Macrophages / drug effects
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / drug effects
  • NF-kappa B / physiology*
  • Ribosomal Protein S6 Kinases, 90-kDa / drug effects
  • Ribosomal Protein S6 Kinases, 90-kDa / physiology*
  • Sepsis / drug therapy*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Imidazoline Receptors
  • NF-kappa B
  • imidazoline receptor 2
  • Agmatine
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3