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

Abstract

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.

The Anti-Inflammatory Role of Omega-3 Polyunsaturated Fatty Acids Metabolites in Pre-Clinical Models of Psychiatric, Neurodegenerative, and Neurological Disorders

“…In three mouse models of depression, RvD2 was shown to have positive effects on depressive-like behavior, however, only one study also investigated cellular outcomes. Central RvD2 administration was reported to improve FST and TST scores in LPS-induced (36) and in a CUS model of depression (39). Similarly, in a model of fibromyalgia-associated depression, intravenous RvD2 prevented immobility in the FST (38).…”

“…However, neither peripheral nor central RvD1 administration improved FST immobility in a mouse fibromyalgia-induced depression model (38), where mice develop depression-like behavior after reserpine injection. In the TST, intracranial RvD1 also reduced behavioral despair in both CUS (39) and lipopolysaccharide (LPS)-induced mouse models of depression (36). Social behavior, commonly affected in depression, was enhanced by intracranial injection of RvD1 in a rat model of depression (37).…”

“…The anti-depressant effects of intracranial administration of RvD1 were shown to be mediated by the activation of the N-formyl peptide receptor 2 (ALX/FPR2). Downstream, RvD1 was shown to act through activation of mammalian target of rapamycin complex Frontiers in Psychiatry | www.frontiersin.org 1(mTORC1), MAP/ERK, PI3K/Akt signaling, as well as by αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (36).…”

“…Among the studies previously mentioned, only one investigated the mechanisms underlying the effects of treatment with RvD2 in a model of depression. In particular, they showed that improvement in depressive-like behavior was observed in mice after intracranial RvD2 administration, which was independently mediated by GPR18, a G-protein-coupled receptor activated by cannabinoids (61) and RvD2, mTORC1, and MAP/ERK signaling (36).…”

Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

“…Additionally, RvD and E are also associated with the prevention of depressivelike behaviors [158]. An intracerebroventricular (icv) injection of RvD1, D2, E1, E2, or E3 significantly decreases LPS-induced depressive-like behaviors [159][160][161]. Moreover, an intrathecal injection of 17R-HDHA prevents the occurrence of depressive-like behaviors and is associated with the decrease of pain perception and a restoration of dopamine and glutamate levels in the brain [149,162].…”