Agmatine Reverses Sub-chronic Stress induced Nod-like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats

Basic Clin Pharmacol Toxicol. 2016 Oct;119(4):367-75. doi: 10.1111/bcpt.12604. Epub 2016 May 10.

Abstract

The activation of Nod-like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)-1β and IL-18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant-like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down-regulated the gene expressions of all stress-induced NLRP3 inflammasome components (NLRP3, NF-κB, PYCARD, caspase-1, IL-1β and IL-18) in the hippocampus and prefrontal cortex (PFC) and reduced pro-inflammatory cytokine levels not only in both brain regions, but also in serum. Stress-reduced levels of IL-4 and IL-10, two major anti-inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress-activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant-like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression.

MeSH terms

  • Agmatine / therapeutic use*
  • Animals
  • Anti-Anxiety Agents / therapeutic use*
  • Antidepressive Agents / therapeutic use*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / chemistry
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Cytokines / antagonists & inhibitors
  • Cytokines / blood
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gene Expression Regulation / drug effects
  • Hippocampus / drug effects
  • Hippocampus / immunology
  • Hippocampus / metabolism
  • Inflammasomes / agonists
  • Inflammasomes / metabolism
  • Male
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects*
  • Neurons / immunology
  • Neurons / metabolism
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / immunology
  • Prefrontal Cortex / metabolism
  • Rats, Sprague-Dawley
  • Restraint, Physical / adverse effects
  • Restraint, Physical / psychology
  • Stress, Physiological / drug effects*
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / immunology
  • Stress, Psychological / metabolism
  • Stress, Psychological / psychology

Substances

  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Cytokines
  • Inflammasomes
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nerve Tissue Proteins
  • Nlrp3 protein, rat
  • Pycard protein, rat
  • Agmatine
  • Caspase 1