Antidepressant-like effects of standardized gypenosides: involvement of brain-derived neurotrophic factor signaling in hippocampus

Psychopharmacology (Berl). 2016 Sep;233(17):3211-21. doi: 10.1007/s00213-016-4357-z. Epub 2016 Jul 6.


Rationale: Gypenosides have been reported to produce neuroprotective effects and increase monoamine neurotransmitter levels in the brain.

Objective: Considering that depression is involved in monoamine reduction, this study evaluated the antidepressant-like effects of gypenosides in mice exposed to chronic unpredictable mild stress (CUMS).

Methods: The sucrose preference test and forced swimming test were performed after administration of gypenosides (at 25, 50, or 100 mg/kg) for 4 weeks. Hippocampal brain-derived neurotrophic factor (BDNF) and its downstream targets were analyzed by western blot. Additionally, hippocampal neuronal proliferation was measured by immunohistochemistry.

Results: Four-week treatment with fluoxetine (20 mg/kg) and gypenosides (at either 50 or 100 mg/kg) increased sucrose preference and decreased the immobility time in mice exposed to CUMS. In addition, gypenosides (at either 50 or 100 mg/kg) also increased BDNF expression and neuronal proliferation in the hippocampus of CUMS animals. Further, we showed that treating CUMS mice with K252a, which is an inhibitor of the BDNF receptor TrkB, blocked the effects of gypenosides (100 mg/kg), including behavioral improvements, neuronal proliferation, and up-regulation of p-TrkB, p-ERK, and p-Akt proteins.

Conclusions: This study demonstrates that gypenosides exhibit antidepressant-like effects in mice, which may be mediated by activation of the BDNF-ERK/Akt signaling pathway in the hippocampus.

Keywords: Brain-derived neurotrophic factor; Chronic unpredictable mild stress; Depression; Gypenosides.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain-Derived Neurotrophic Factor / drug effects*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Carbazoles / pharmacology
  • Depression
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluoxetine / pharmacology
  • Gynostemma
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Indole Alkaloids / pharmacology
  • Male
  • Mice
  • Phosphorylation / drug effects
  • Plant Extracts / pharmacology
  • Proto-Oncogene Proteins c-akt / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, trkB / antagonists & inhibitors
  • Receptor, trkB / drug effects
  • Receptor, trkB / metabolism
  • Signal Transduction / drug effects
  • Stress, Psychological / metabolism*
  • Stress, Psychological / psychology
  • Sucrose / administration & dosage
  • Sweetening Agents / administration & dosage
  • Swimming
  • Up-Regulation / drug effects


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Carbazoles
  • Enzyme Inhibitors
  • Indole Alkaloids
  • Plant Extracts
  • Sweetening Agents
  • gypenoside
  • Fluoxetine
  • Sucrose
  • staurosporine aglycone
  • Receptor, trkB
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases