Nonenzymatic oxygenated metabolite of docosahexaenoic acid, 4(RS)-4-F4t-neuroprostane, acts as a bioactive lipid molecule in neuronal cells

Docosahexaenoic acid (DHA), an abundant fatty acid in the brain, is susceptible to auto-oxidation in situ and releases metabolites such as F-4-neuroprostane (4-F-4t-NeuroP). The presence of 4-F-4t-NeuroP in the brain is not well explored. In this study, 4-F-4t-NeuroP was introduced into neuroblastoma cells (SH-SY5Y) and, by in vivo infusion, into rodents. Targeted lipidomic analysis of liver and brain tissues shows significant elevation of anti-inflammatory hydroxylated DHA metabolites and an isomer of neuroprotectin D1, suggesting potential beneficial bioactivities of 4-F-4t-NeuroP. Additionally, 4-F-4t-NeuroP treatment in SH-SY5Y cells and primary neuronal culture consistently upregulates the transcriptional level of the antioxidant enzyme heme oxygenase-1, but the effect is reduced when 4-F-4t-NeuroP is further oxidized. Our data suggest that 4-F-4t-NeuroP could be neuroprotective in the native state but may have disadvantageous bioactivity when oxidized extensively.