docosapentaenoic-acid and Neuroblastoma

The omega-3 fatty acid docosahexaenoic acid (DHA n-3) has long been known to be a major component of phosphoglycerides in the gray matter of mammalian brains. Furthermore, early studies of synaptosomes that had been isolated from gray matter showed that the plasma membranes of the synaptosomes contained DHA n-3 that was selectively esterified to phosphatidylethanolamine, plasmenylethanolamine (alkenylacyl-glycero-phosphorylethanolamine), and phosphatidylserine. In contrast, the phosphatidylcholine in these membranes contained esterified oleic acid, and the sphingomyelin and glycolipids in the membranes contained amide-linked stearic acid instead of a mixture of this acid with other, amide-linked fatty acids. The full implications of this unusual distribution of lipid head groups, esterified fatty acids, and amide-linked fatty acids are unclear, but the phosphoglycerides and sphingosine-containing lipids appear to be distributed asymmetrically between the two leaflets of the plasma membrane lipid bilayer and are likely to contribute to a dynamic lipid substructure. Because very few neuronal plasma membranes have been isolated and characterized to date, a major challenge for the future will be to investigate the composition of the lipid bilayers of different neuronal plasma membranes and identify effects of DHA n-3-containing phosphoglycerides on the ability of the plasma membranes to perform their many different functions. The aim of this Perspective is to stimulate further work in this important area by discussing recent evidence related to the role of neuronal plasma membrane phosphoglycerides in cell signaling.

Topics: Animals; Cell Line, Tumor; Cerebral Cortex; CHO Cells; Cricetinae; Cricetulus; Culture Media, Serum-Free; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Glycerophospholipids; Insulin-Like Growth Factor I; Mammals; Membrane Lipids; Mice; Neuroblastoma; Neurons; Nitrogenous Group Transferases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf; Rats; Serine; Spectrin; Substrate Specificity

Whether neurosteroids regulate the synthesis of long chain polyunsaturated fatty acids in brain cells is unknown. We examined the influence of 17-beta-estradiol (E2) on the capacity of SH-SY5Y cells supplemented with alpha-linolenic acid (ALA), to produce eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). Cells were incubated for 24 or 72 h with ALA added alone or in combination with E2 (ALA + E2). Fatty acids were analyzed by gas chromatography of ethanolamine glycerophospholipids (EtnGpl) and phosphatidylcholine (PtdCho). Incubation for 24 h with ALA alone increased EPA and DPA in EtnGpl, by 330 and 430% compared to controls (P < 0.001) and DHA by only 10% (P < 0.05). Although DHA increased by 30% (P < 0.001) in ALA + E2-treated cells, the difference between the ALA and ALA + E2 treatments were not significant after 24 h (Anova-1, Fisher's test). After 72 h, EPA, DPA and DHA further increased in EtnGpl and PtdCho of cells supplemented with ALA or ALA + E2. Incubation for 72 h with ALA + E2 specifically increased EPA (+34% in EtnGpl, P < 0.001) and DPA (+15%, P < 0.001) compared to ALA alone. Thus, SH-SY5Y cells produced membrane EPA, DPA and DHA from supplemental ALA. The formation of DHA was limited, even in the presence of E2. E2 significantly favored EPA and DPA production in cells grown for 72 h. Enhanced synthesis of ALA-elongation products in neuroblastoma cells treated with E2 supports the hypothesis that neurosteroids could modulate the metabolism of PUFA.

Topics: alpha-Linolenic Acid; Cell Line, Tumor; Cell Proliferation; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Estradiol; Fatty Acids, Unsaturated; Humans; Neuroblastoma; Phospholipids; Tumor Cells, Cultured

We previously established that n-3 FA status in membrane phospholipids influences the biosynthesis and accumulation of PS in neuronal tissues. We also demonstrated that neuronal apoptosis under adverse conditions is prevented by DHA enrichment in a PS-dependent manner. In this study, we examined the effect of a structural analog of DHA, docosapentaenoic acid (22:5n-6, DPA), which accumulates in neuronal membranes during n-3 FA deficiency. We observed that enrichment of neuronal cells with DPA increased the total PS content in comparison to nonenriched control. However, the increase was significantly less than that observed in DHA-enriched cells, primarily due to the fact that the 18:0,22:5n-6 species was not accumulated as effectively as 18:0,22:6n-3 in PS. As was the case with DHA, DPA enrichment also protected against cell death induced by staurosporine treatment in Neuro 2A cells, but to a lesser extent. These data indicate that provision of DPA in place of DHA is sufficient neither for fully supporting PS accumulation nor for cell survival. The in vitro interaction between Raf-1 and membrane was affected not only by the PS content but also by the fatty acyl composition in PS. The reduction of PS concentration as well as the substitution of 18:0,22:6 with 16:0,18:1 in the liposome considerably reduced the interaction with Raf-1. These data suggest that depletion of DHA from neuronal tissues may have a compounding effect on Raf-1 translocation in growth factor signaling. The fact that DPA cannot fully support the protective role played by DHA may provide a basis for the adverse effect of n-3 FA deficiency on neuronal development and function.

Topics: Animals; Apoptosis; Caspases; Cell Line, Tumor; Cytoprotection; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Mice; Neuroblastoma; Neurons; Neuroprotective Agents; Phosphatidylserines; Proto-Oncogene Proteins c-raf; Staurosporine; Tissue Distribution