Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway

Metab Brain Dis. 2016 Aug;31(4):837-48. doi: 10.1007/s11011-016-9809-y. Epub 2016 Mar 5.


Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress.

Keywords: Depression; Forced swimming; Monoamine; Piperine; Trans-resveratrol; cAMP signaling.

MeSH terms

  • Alkaloids / pharmacology*
  • Animals
  • Behavior, Animal / drug effects*
  • Benzodioxoles / pharmacology*
  • Cyclic AMP / metabolism*
  • Depression / metabolism*
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Male
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Resveratrol
  • Signal Transduction / drug effects
  • Stilbenes / pharmacology*
  • Stress, Psychological / metabolism*


  • Alkaloids
  • Benzodioxoles
  • Piperidines
  • Polyunsaturated Alkamides
  • Stilbenes
  • Cyclic AMP
  • Resveratrol
  • piperine