N-Docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling

Abstract

BackgroundBrain inflammation has been implicated as a critical mechanism responsible for the progression of neurodegeneration and characterized by glial cell activation accompanied by production of inflammation-related cytokines and chemokines. Growing evidence also suggests that metabolites derived from docosahexaenoic acid (DHA) have anti-inflammatory and pro-resolving effects; however, the possible role of N-docosahexaenoylethanolamine (synaptamide), an endogenous neurogenic and synaptogenic metabolite of DHA, in inflammation, is largely unknown. (The term “synaptamide” instead of “DHEA” was used for N-docosahexaenoylethanolamine since DHEA is a widely used and accepted term for the steroid, dehydroepiandrosterone.) In the present study, we tested this possibility using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo.MethodsFor in vitro studies, we used P3 primary rat microglia and immortalized murine microglia cells (BV2) to assess synaptamide effects on LPS-induced cytokine/chemokine/iNOS (inducible nitric oxide synthase) expression by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). To evaluate in vivo effects, mice were intraperitoneally (i.p.) injected with LPS followed by synaptamide, and expression of proinflammatory mediators was measured by qPCR and western blot analysis. Activation of microglia and astrocyte in the brain was examined by Iba-1 and GFAP immunostaining.ResultsSynaptamide significantly reduced LPS-induced production of TNF-α and NO in cultured microglia cells. Synaptamide increased intracellular cAMP levels, phosphorylation of PKA, and phosphorylation of CREB but suppressed LPS-induced nuclear translocation of NF-κB p65. Conversely, adenylyl cyclase or PKA inhibitors abolished the synaptamide effect on p65 translocation as well as TNF-α and iNOS expression. Administration of synaptamide following LPS injection (i.p.) significantly reduced neuroinflammatory responses, such as microglia activation and mRNA expression of inflammatory cytokines, chemokine, and iNOS in the brain.ConclusionsDHA-derived synaptamide is a potent suppressor of neuroinflammation in an LPS-induced model, by enhancing cAMP/PKA signaling and inhibiting NF-κB activation. The anti-inflammatory capability of synaptamide may provide a new therapeutic avenue to ameliorate the inflammation-associated neurodegenerative conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0751-z) contains supplementary material, which is available to authorized users.

Acyl-CoA synthetase 6 enriches the neuroprotective omega-3 fatty acid DHA in the brain

“…DHA has received recent attention for its antiinflammatory properties (9)(10)(11)(38)(39)(40). However, not all reports are consistent with reduced neuroinflammation by DHA (27)(28)(29)(30)(31)(41)(42)(43). Because dietary DHA manipulation involves whole-body metabolism of DHA, the neuroprotective effects could be elicited by responses outside the central nervous system.…”

Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation

“…In addition to its function as a unique building block of cell membranes, DHA is also a precursor for docosanoids and other bioactive endogenous derivatives in the neural tissue [37]. The number of recently identified DHA derivatives in neural tissue is increasingly growing and includes neuroprotectin D1 (NPD1), synaptamide, endocannabinoid epoxides, and elovanoids [38][39][40]. Collectively, the potent bioactive properties of these DHA derivatives contribute to preservation of normal neuronal function, tissue homeostasis, and neuronal survival [37][38][39][40][41].…”

“…The number of recently identified DHA derivatives in neural tissue is increasingly growing and includes neuroprotectin D1 (NPD1), synaptamide, endocannabinoid epoxides, and elovanoids [38][39][40]. Collectively, the potent bioactive properties of these DHA derivatives contribute to preservation of normal neuronal function, tissue homeostasis, and neuronal survival [37][38][39][40][41]. In addition, the DHA derivatives exert a range of potent neuroprotective properties that include inhibition of proinflammatory gene expression and leukocyte infiltration.…”

“…A striking hallmark of the DHA derivatives is their ability to potentiate microglial polarization from a proinflammatory phenotype to a surveillance-repair state and reduce NF-kB-mediated expression of inflammatory cytokines in the brain. Moreover, DHA derivatives contribute to BBB integrity and are neurogenic and synaptogenic [38,42]. Thus, the DHA derivatives seem to be key mediators of the resolution of inflammation and recovery of homeostasis in the CNS microenvironment.…”

The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology

“…Cyclic AMP in turn represents the second messengers of many G-protein mediated hormone and cytokine responses [154] (e.g., induction of hepatic glycogenolysis after β-adrenergic stimulation [155]), processes of cell differentiation, cytoskeletal remodeling and proliferation in addition to apoptosis and immune modulation [156]. While AGE formation is thought to be part of pro-inflammatory signaling cascades (via RAGE and NFκB), recent in vivo studies suggest that globally high cAMP concentrations have moderate immunosuppressive effects [157,158]. Furthermore, cAMP-impaired neutrophil chemotaxis in vitro [159] decreased the release of histamine and leukotrienes from basophils or mast cells [160], which significantly reduced ROS formation [161,162].…”