Plant Natural Product Puerarin Ameliorates Depressive Behaviors and Chronic Pain in Mice with Spared Nerve Injury (SNI)

Mol Neurobiol. 2017 May;54(4):2801-2812. doi: 10.1007/s12035-016-9870-x. Epub 2016 Mar 24.


Simultaneous relief of the pain from body and brain remains an ongoing challenge. The aim of the present study was to clarify whether plant-derived isoflavone puerarin could ameliorate comorbid depression and pain. We investigated the effects of puerarin on depressive-like behaviors and neuropathic pain in C57BL/6 N mice with spared nerve injury (SNI). After SNI surgery, mice were allowed to recover spontaneously for 7 days and subsequently treated with puerarin, anti-depressant citalopram, and analgesic ibuprofen, alone or in combination, for 8 or 14 days. Forced swim test and tail suspension test were used to assess depressive-like behaviors, whereas von Frey filament test was used to estimate the sensitivity to the mechanical stimulation. Our results suggested that puerarin effectively ameliorated depression and pain in SNI mice although citalopram exhibited anti-depressant activity. In contrast, ibuprofen showed lesser activities against SNI-induced depression and pain. Further mechanistic studies revealed the uniqueness of puerarin as follows: (1) puerarin did not recover SNI-induced depletion of reduced glutathione and loss of superoxide dismutase (SOD), whereas citalopram and ibuprofen showed somewhat antioxidant activities; (2) puerarin markedly promoted the activation of CREB pathway although puerarin and citalopram activated ERK pathway to the same extent; (3) puerarin rapidly and persistently induced brain-derived neurotrophic factor (BDNF) expression whereas citalopram only induced BDNF expression after a prolonged stimulation. Collectively, these results suggest that puerarin may ameliorate the SNI-induced depression and pain via activating ERK, CREB, and BDNF pathways. Puerarin may serve as new lead compound for the development of novel therapeutics for depression and pain comorbidity.

Keywords: BDNF; Depression; Pain; Puerarin; Spared nerve injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Biological Products / pharmacology
  • Biological Products / therapeutic use*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Chronic Pain / complications*
  • Chronic Pain / drug therapy*
  • Chronic Pain / pathology
  • Citalopram / pharmacology
  • Citalopram / therapeutic use
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Depression / complications*
  • Depression / drug therapy*
  • Depression / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluorescent Antibody Technique
  • Ibuprofen / pharmacology
  • Ibuprofen / therapeutic use
  • Isoflavones / pharmacology
  • Isoflavones / therapeutic use*
  • Male
  • Mice, Inbred C57BL
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / injuries*
  • Sciatic Nerve / pathology


  • Antidepressive Agents
  • Biological Products
  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Isoflavones
  • Citalopram
  • Extracellular Signal-Regulated MAP Kinases
  • Ibuprofen
  • puerarin