Resolvin E1/E2 ameliorate lipopolysaccharide-induced depression-like behaviors via ChemR23
- 458 Downloads
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.
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.
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.
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.
KeywordsChemerin ChemR23 Dentate gyrus Depression Medial prefrontal cortex mTORC1 Resolvin
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Franklin KBJ, Paxinos G (2007) The mouse brain in stereotaxic coordinates, 3rd edn. Elsevier, Burlington, MAGoogle Scholar
- Frenois F, Moreau M, O’Connor J, Lawson M, Micon C, Lestage J, Kelley KW, Dantzer R, Castanon N (2007) Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516–531CrossRefPubMedPubMedCentralGoogle Scholar
- Fukuda H, Muromoto R, Takakura Y, Ishimura K, Kanada R, Fushihara D, Tanabe M, Matsubara K, Hirao T, Hirashima K, Abe H, Arisawa M, Matsuda T, Shuto S (2016) Design and synthesis of cyclopropane congeners of resolvin E2, an endogenous proresolving lipid mediator, as its stable equivalents. Org Lett 18:6224–6227CrossRefPubMedGoogle Scholar
- Harrison JL, Rowe RK, Ellis TW, Yee NS, O'Hara BF, Adelson PD, Lifshitz J (2015) Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse. Brain Behav Immun 47:131–140CrossRefPubMedPubMedCentralGoogle Scholar
- Ishimura K, Fukuda H, Watanabe M, Shuto S (2016) Efficient synthesis of anti-inflammatory lipid mediator resolvin E1 and its analogues. EFMC International Symposium of Medicinal Chemistry, Book of Abstract, p589Google Scholar
- Jiang Y, Liu P, Jiao W, Meng J, Feng J (2017) Gax suppresses chemerin/CMKLR1-induced preadipocyte biofunctions through the inhibition of Akt/mTOR and ERK signaling pathways. J Cell Physiol in pressGoogle Scholar
- Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, Burgdorf J, Moskal J, Taylor J, Aghajanian G, Duman RS (2016) GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. NeuropsychopharmacologyGoogle Scholar
- Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM, Group G-CS (2015) Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract 21:140–149CrossRefPubMedGoogle Scholar
- Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, Team SDS (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40CrossRefPubMedGoogle Scholar
- Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R, Sanacora G, Eid T, Aghajanian G, Duman RS (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742–749CrossRefPubMedGoogle Scholar