N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2

Abstract

Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E (PGE) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology

“…N-docosahexaenoyl dopamine dose-dependently (1 or 2 mM) inhibits LPSinduced IL-6 and CCL20 production in BV2 cells, whereas neither DHA nor dopamine alone (at the same, low concentrations, 1 or 2 mM) is able to produce the same effects. This was paralleled by a decreased production of PGE 2 , whereas COX-2 gene expression remained stable (Wang et al, 2017).…”

“…Besides oxidation, DHA can be conjugated with alcohols and amines to form esters and amides, respectively (Kuda, 2017). Among all DHA conjugates, the amine conjugate N-docosahexaenoyl dopamine has been shown to modulate microglial function in vitro (BV2 cells) (Wang et al, 2017). N-docosahexaenoyl dopamine dose-dependently (1 or 2 mM) inhibits LPSinduced IL-6 and CCL20 production in BV2 cells, whereas neither DHA nor dopamine alone (at the same, low concentrations, 1 or 2 mM) is able to produce the same effects.…”

n–3 Polyunsaturated Fatty Acid Amides: New Avenues in the Prevention and Treatment of Breast Cancer

“…Dang and coworkers demonstrated that compounds bearing a dopamine head group were the most active in reducing pro-inflammatory markers among a series of structural analogues [60]. In rodent macrophages and microglia cells, DHADA suppressed in a concentration-dependent manner the protein levels of pro-inflammatory markers, such as NO, MCP-1, macrophage-inflammatory protein 3α (MIP3A or CCL20), IL-6 as well as levels of prostaglandin E2 (PGE2), which is a cyclooxygenase-2 (COX-2) product that promotes inflammation [61]. These findings suggest that DHA and dopamine, the most abundant fatty acid and an important neurotransmitter in the brain, could combine in a lipid mediator conjugate able to modulate neuro-inflammation.…”

Microglia and its role in neurodegenerative diseases

“…They stated that this receptor could be a clinical biomarker for PD, and a therapeutic approach to the disease thanks to receptor blockers (Yang et al, 2017). It is reported in the literature that progressive degeneration of dopaminergic neurons is further increased with excessive increase in microglial cell activation (Wang et al, 2017). A significant relationship was found between serum samples from PD and low vitamin D levels.…”