Honokiol abrogates chronic restraint stress-induced cognitive impairment and depressive-like behaviour by blocking endoplasmic reticulum stress in the hippocampus of mice

Eur J Pharmacol. 2016 Jan 5:770:25-32. doi: 10.1016/j.ejphar.2015.11.047. Epub 2015 Nov 27.


The primary objective of our study is to investigate the neuroprotective efficacy of honokiol and imipramine against restraint stress (RS)-induced cognitive impairment and depressive-like behaviour in mice. We examined whether the neuroprotective activity of honokiol and imipramine mediates through the inhibition of endoplasmic reticulum stress. Adult Swiss albino mice were restrained for 6h/day for 28 days. Honokiol (3 and 10mg/kg) and Imipramine (10 and 30mg/kg) were administered for last 7 days to the different groups. Cognitive function was assessed by Morris water maze and novel object recognition test. Forced swimming test and tail suspension test were performed to evaluate the restraint stress-induced depressive-like behaviour. Proinflammatory cytokines, brain-derived neurotrophic factor, and ER stress markers i.e. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) were quantified in the hippocampus. We observed cognitive impairment and depressive-like behaviour in RS-exposed animals. Honokiol (10mg/kg) treated group depicted marked reduction in cognitive impairment and depressive-like behaviour. However, imipramine (10 and 30mg/kg) prevented the depressive-like behaviour but failed to prevent RS-induced cognitive impairment. Moreover, proinflammatory cytokines, GRP78 and CHOP were elevated in the hippocampus of stressed mice as compared to unstressed mice. Honokiol (10mg/kg) significantly prevented the RS-induced elevated levels of proinflammatory cytokines and endoplasmic reticulum stress markers. Our results clearly suggest the beneficial potential of honokiol in restraint stress through inhibition of proinflammatory cytokines and endoplasmic reticulum stress. Honokiol could be an intriguing therapeutic approach in endoplasmic reticulum stress related neuro-pathophysiological conditions.

Keywords: Cognitive impairment; Depressive-like behaviour; Endoplasmic reticulum stress; Honokiol; Imipramine; Restraint stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Biphenyl Compounds / pharmacology*
  • Biphenyl Compounds / therapeutic use
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / metabolism
  • Cognition Disorders / pathology
  • Cognition Disorders / psychology
  • Cytokines / metabolism
  • Depression / drug therapy*
  • Depression / metabolism
  • Depression / pathology
  • Depression / psychology
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / drug effects*
  • Gene Expression Regulation / drug effects
  • Heat-Shock Proteins / genetics
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Imipramine / pharmacology
  • Lignans / pharmacology*
  • Lignans / therapeutic use
  • Male
  • Mice
  • Restraint, Physical / psychology
  • Stress, Psychological / complications*
  • Transcription Factor CHOP / genetics


  • Biphenyl Compounds
  • Brain-Derived Neurotrophic Factor
  • Cytokines
  • Ddit3 protein, mouse
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Lignans
  • honokiol
  • Transcription Factor CHOP
  • Imipramine