N-Docosahexaenoylethanolamine ameliorates LPS-induced brain inflammation through suppression of microglia cell activation as well as proinflammatory mediators expression

Authors

• TY Park
• H Chen
• JW Lee
• Karl Kevara
• HY Kim

Abstract

Synaptamide (N-docosahexaenoylethanolamine) is synthesized from docosahexaenoic acid (DHA) in the brain and potently induces neurite growth and synaptogenesis in developing neurons and neurogenic differentiation of neural stem cells (NSCs). Growing evidence also suggests that DHA-derived metabolites have anti-inflammatory and pro-resolving effects, however, the role of synaptamide in the brain inflammation is unknown. Herein, we investigated whether the intraperitoneal injection or exogenous treatment of synaptamide with lipopolysaccharide (LPS) is associated with changes in the pro-inflammatory (TNF-α, IL-1β, IL-6, CCL2, and iNOS) and anti-inflammatory (IL-10) mediators and glial cell activation in the mice brain and cultured microglial cells. Treatment of synaptamide significantly reduces LPS-induced production of TNF-α and Nitric oxide (NO) in microglia cells with concomitant induction of cAMP/PKA phosphorylation. Conversely, adenylyl cyclase or PKA inhibitors abolished the synaptamide effect on TNF-α and iNOS expression. Furthermore, intraperitoneally administered synaptamide almost significantly suppresses brain inflammatory response, including morphological activation of microglial cells, mRNA expression of inflammatory cytokines, chemokine and iNOS in the brain. In this study, we revealed that the effects of synaptamide on LPS-induced inflammation in mouse brains and microglia along with underlying signaling mechanisms. We found that synaptamide potently inhibits LPS-induced pro-inflammatory cytokine/chemokine production and nuclear translocation of p65 in microglia cells through upregulating cAMP/PKA signaling. In vivo injection of synaptamide significantly suppressed LPS-induced microglia activation and almost completely abolished cytokine production in mouse brains. The anti-neuroinflammatory effects of synaptamide demonstrated in our study suggest a potential new therapeutic avenue for treating neurodegeneration and brain injury.

Scientific Focus Area: Neuroscience

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