Vaccinium myrtillus ameliorates unpredictable chronic mild stress induced depression: possible involvement of nitric oxide pathway

Phytother Res. 2012 Apr;26(4):488-97. doi: 10.1002/ptr.3584. Epub 2011 Aug 26.


Chronic unpredictable stressors can produce a situation similar to clinical depression and such animal models can be used for the preclinical evaluation of antidepressants. Nitric oxide, a secondary messenger molecule, has been implicated in neurotransmission, synaptic plasticity, learning, aggression and depression. Vaccinium myrtillus (bilberry) extract is a potent inhibitor of reactive oxygen/nitrogen species and cytokine production. The present study investigated the role of nitric oxide in the antidepressant action of Vaccinium myrtillus in unpredictable chronic mild stress-induced depression in mice. Animals were subjected to different stress paradigms daily for a period of 21 days to induce depressive-like behavior. Pretreatment with L-arginine significantly reversed the protective effect of bilberry (500 mg/kg) on chronic stress-induced behavioral (immobility period, sucrose preference) and biochemical (lipid peroxidation and nitrite levels; endogenous antioxidant activities) in stressed mice. Furthermore, L-NAME (10 mg/kg) pretreatment with a sub-effective dose of bilberry (250 mg/kg) significantly potentiated the protective effect of bilberry extract. The study revealed that modulation of the nitric oxide pathway might be involved in antidepressant-like effects of Vaccinium myrtillus in stressed mice.

MeSH terms

  • Animals
  • Anthocyanins / administration & dosage
  • Anthocyanins / pharmacology*
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology
  • Arginine / adverse effects
  • Behavior, Animal / drug effects*
  • Depression / drug therapy*
  • Dose-Response Relationship, Drug
  • Lipid Peroxidation
  • Male
  • Mice
  • Motor Activity
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism
  • Phytotherapy
  • Plant Extracts
  • Reactive Oxygen Species / metabolism
  • Stress, Physiological*
  • Vaccinium myrtillus / chemistry*


  • Anthocyanins
  • Antidepressive Agents
  • Plant Extracts
  • Reactive Oxygen Species
  • Nitric Oxide
  • Vaccinium myrtillus extract
  • Arginine
  • NG-Nitroarginine Methyl Ester