Resolvin E3 attenuates lipopolysaccharide-induced depression-like behavior in mice.

Eicosapentaenoic acid (EPA)-derived resolvin E1 (RvE1) and E2 (RvE2) have antidepressant effects. Here, we investigated the antidepressant effects of resolvin E3 (RvE3) in a mouse model of lipopolysaccharide (LPS)-induced depression. We observed that LPS (0.8 mg/kg, i.p.) significantly increased immobility time on the tail suspension test, and this depression-like behavior was dose-dependently attenuated by intracerebroventricular infusion of RvE3 (10 or 100 ng). No effects of LPS or intracerebroventricular infusion of RvE3 on locomotor activity were observed. These results indicate that RvE3, as well as RvE1 and RvE2, have antidepressant effects.

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

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.

Rapid and sustained antidepressant effects of resolvin D1 and D2 in a chronic unpredictable stress model.

Resolvin D1 (RvD1) and D2 (RvD2) are lipid mediators that are derived from docosahexaenoic acid. We recently demonstrated that intracerebroventricular (i.c.v.) infusions of RvD1 or RvD2 attenuate lipopolysaccharide-induced depression-like behaviors via mammalian target of rapamycin complex 1 signaling. However, the antidepressant effects of RvD1 and RvD2 have not been fully investigated. Here, we examined the antidepressant effects of RvD1 and RvD2 using the tail suspension test (TST) and forced swim test (FST) in murine chronic unpredictable stress (CUS) model. Male BALB/c mice (7 weeks) were subjected to 5 weeks of CUS and then received with a single i.c.v. infusion of RvD1 (10ng), RvD2 (10ng), or vehicle. In vehicle-infused mice, CUS significantly increased immobility in the TST both 2 and 24h after i.c.v. infusion, these depression-like behaviors were significantly ameliorated by RvD1 or RvD2. Similar results were obtained from the FST. Intracerebroventricular infusion of RvD1 or RvD2 did not affect locomotor activity. These results demonstrate that RvD1 and RvD2 produce rapid and sustained antidepressant effects in the CUS model.

Resolvin D1 and D2 Reverse Lipopolysaccharide-Induced Depression-Like Behaviors Through the mTORC1 Signaling Pathway.

Background: Resolvin D1 and D2 are bioactive lipid mediators that are generated from docosahexaenoic acid. Although recent preclinical studies suggest that these compounds have antidepressant effects, their mechanisms of action remain unclear. Methods: We investigated mechanisms underlying the antidepressant effects of resolvin D1 and resolvin D2 in lipopolysaccharide (0.8 mg/kg, i.p.)-induced depression model mice using a tail suspension test. Results: I.c.v. infusion of resolvin D1 (10 ng) and resolvin D2 (10 ng) produced antidepressant effects; these effects were significantly blocked by a resolvin D1 receptor antagonist WRW4 (10 µg, i.c.v.) and a resolvin D2 receptor antagonist O-1918 (10 µg, i.c.v.), respectively. The mammalian target of rapamycin complex 1 inhibitor rapamycin (10 mg/kg, i.p.) and a mitogen-activated protein kinase kinase inhibitor U0126 (5 µg, i.c.v.) significantly blocked the antidepressant effects of resolvin D1 and resolvin D2. An AMPA receptor antagonist NBQX (10 mg/kg, i.p.) and a phosphoinositide 3-kinase inhibitor LY294002 (3 µg, i.c.v.) blocked the antidepressant effects of resolvin D1 significantly, but not of resolvin D2. Bilateral infusions of resolvin D1 (0.3 ng/side) or resolvin D2 (0.3 ng/side) into the medial prefrontal cortex or dentate gyrus of the hippocampus produced antidepressant effects. Conclusions: These findings demonstrate that resolvin D1 and resolvin D2 produce antidepressant effects via the mammalian target of rapamycin complex 1 signaling pathway, and that the medial prefrontal cortex and dentate gyrus are important brain regions for these antidepressant effects. These compounds and their receptors may be promising targets for the development of novel rapid-acting antidepressants, like ketamine and scopolamine.