Resolvin E1/E2 ameliorate lipopolysaccharide-induced depression-like behaviors via ChemR23

Psychopharmacology (Berl). 2018 Jan;235(1):329-336. doi: 10.1007/s00213-017-4774-7. Epub 2017 Oct 31.


Rationale: Resolvins are bioactive lipid mediators that are generated from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). We recently demonstrated that the DHA-derived resolvins D1 and D2 exert antidepressant effects. However, whether the EPA-derived resolvins E1 (RvE1) and E2 (RvE2) produce antidepressant effects is not clear.

Objectives: We examined the antidepressant effects of RvE1/RvE2 in a murine lipopolysaccharide (LPS)-induced depression model using the tail suspension and forced swim tests. RvE1/RvE2 reportedly possesses both chemerin receptor ChemR23 agonistic activity and leukotriene B4 receptor BLT1 antagonistic activity. Therefore, we investigated the receptor involved in its antidepressant effects. We also examined the roles of the mammalian target of rapamycin complex 1 (mTORC1) in the antidepressant effect of RvE1 as well as the effects of RvE1 infusions into the medial prefrontal cortex (mPFC) and hippocampal dentate gyrus (DG) on LPS-induced depression-like behaviors.

Results: Intracerebroventricular infusions of RvE1 (1 ng)/RvE2 (10 ng) produced significant antidepressant effects. An intracerebroventricular infusion of chemerin (500 ng), but not U75302 (a BLT1 antagonist; 10 or 50 ng), produced antidepressant effects. Intraperitoneal rapamycin (an mTORC1 inhibitor; 10 mg/kg) blocked the antidepressant effect of intracerebroventricular RvE1. Bilateral intra-mPFC and intra-DG infusions of RvE1 (50 pg/side) exerted antidepressant effects.

Conclusions: The results of this study demonstrate that (1) RvE1/RvE2 produce antidepressant effects likely via ChemR23, (2) mTORC1 signaling mediates the antidepressant effect of RvE1, and (3) mPFC and DG are the key brain regions involved in these actions. RvE1/RvE2 and their receptors may be promising targets for the development of novel antidepressants.

Keywords: ChemR23; Chemerin; Dentate gyrus; Depression; Medial prefrontal cortex; Resolvin; mTORC1.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain / drug effects
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / physiopathology
  • Disease Models, Animal
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid / analogs & derivatives*
  • Eicosapentaenoic Acid / pharmacology
  • Fatty Alcohols / pharmacology
  • Glycols / pharmacology
  • Hindlimb Suspension / physiology
  • Lipopolysaccharides / toxicity
  • Locomotion / drug effects*
  • Male
  • Mice
  • Prefrontal Cortex / drug effects
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Swimming
  • TOR Serine-Threonine Kinases / physiology


  • Antidepressive Agents
  • Fatty Alcohols
  • Glycols
  • Lipopolysaccharides
  • resolvin E2
  • U 75302
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • TOR Serine-Threonine Kinases
  • 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
  • Sirolimus