Agmatine attenuates chronic unpredictable mild stress-induced anxiety, depression-like behaviours and cognitive impairment by modulating nitrergic signalling pathway

Brain Res. 2017 May 15;1663:66-77. doi: 10.1016/j.brainres.2017.03.004. Epub 2017 Mar 14.


Agmatine, a neurotransmitter/neuromodulator, has shown to exert numerous effects on the CNS. Chronic stress is a risk factor for development of depression, anxiety and deterioration of cognitive performance. Compelling evidences indicate an involvement of nitric oxide (NO) pathway in these disorders. Hence, investigation of the beneficial effects of agmatine on chronic unpredictable mild stress (CUMS)-induced depression, anxiety and cognitive performance with the involvement of nitrergic pathway was undertaken. Mice were subjected to a battery of stressors for 28days. Agmatine (20 and 40mg/kg, i.p.) alone and in combination with NO modulators like L-NAME (15mg/kg, i.p.) and l-arginine (400mg/kg i.p.) were administered daily. The results showed that 4-weeks CUMS produces significant depression and anxiety-like behaviour. Stressed mice have also shown a significant high serum corticosterone (CORT) and low BDNF level. Chronic treatment with agmatine produced significant antidepressant-like behaviour in forced swim test (FST) and sucrose preference test, whereas, anxiolytic-like behaviour in elevated plus maze (EPM) and open field test (OFT) with improved cognitive impairment in Morris water maze (MWM). Furthermore, agmatine administration reduced the levels of acetylcholinesterase and oxidative stress markers. In addition, agmatine treatment significantly increased the BDNF level and inhibited serum CORT level in stressed mice. Treatment with L-NAME (15mg/kg) potentiated the effect of agmatine whereas l-arginine abolished the anxiolytic, antidepressant and neuroprotective effects of agmatine. Agmatine showed marked effect on depression and anxiety-like behaviour in mice through nitrergic pathway, which may be related to modulation of oxidative-nitrergic stress, CORT and BDNF levels.

Keywords: Agmatine; Anxiety; BDNF; CUMS; Depression; HPA axis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agmatine / metabolism
  • Agmatine / pharmacokinetics
  • Agmatine / pharmacology*
  • Agmatine / therapeutic use*
  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Antidepressive Agents / pharmacology
  • Anxiety / drug therapy
  • Anxiety / etiology
  • Anxiety / metabolism
  • Behavior, Animal / drug effects
  • Chronic Disease
  • Cognition Disorders / drug therapy
  • Cognitive Dysfunction
  • Corticosterone / blood
  • Depression / drug therapy
  • Depression / etiology
  • Depressive Disorder / drug therapy
  • Hippocampus / metabolism
  • Male
  • Maze Learning / drug effects
  • Mice
  • NG-Nitroarginine Methyl Ester / metabolism
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Signal Transduction / drug effects
  • Stress, Psychological / metabolism


  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Agmatine
  • NG-Nitroarginine Methyl Ester
  • Corticosterone