N‐Docosahexaenoylethanolamine ameliorates LPS‐induced brain inflammation through suppression of neutrophil/macrophage as well as microglia activation

Abstract

Inflammation is a widely accepted common factor among various neuropathological processes and has been implicated as a critical mechanism responsible for the progression of neurodegeneration. Brain inflammation is characterized by glial cell activation accompanied by production of inflammation‐related cytokines, chemokines and nitric oxide (NO).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. Thus, we investigated synaptamide effects on lipopolysaccharide (LPS)‐induced cytokine, chemokines, and iNOS expression in the brain, along with possible mechanisms.We found that synaptamide significantly reduces LPS‐induced production of TNF‐α and Nitric oxide in microglia cells with concomitant induction of cAMP/PKA phosphorylation. Conversely, adenylyl cyclase or PKA inhibitors abolished the synaptamide effect on TNF‐α expression. More importantly, we found that in vivo administration of synaptmide almost completely suppresses brain inflammatory response, including morphological activation of microglia and astrocytes, mRNA expression of inflammatory cytokines, chemokine and iNOS in the brain. Interestingly, we also found that synaptamide exerts anti‐inflammatory effect on neutrophil and macrophage cells. Taken together, our findings suggest that synaptamide can reduce LPS‐induced brain inflammation through suppression of microglia, neutrophil and macrophage activation. The synaptamide‐mediated mechanism contributes to the protective effects of DHA against neuroinflammation, and may provide a new therapeutic target to ameliorate the inflammation‐induced brain dysfunction.