Nonenzymatic oxygenated metabolite of docosahexaenoic acid, 4(RS)‐4‐F_4t‐neuroprostane, acts as a bioactive lipid molecule in neuronal cells

Abstract

Docosahexaenoic acid (DHA), an abundant fatty acid in the brain, is susceptible to auto‐oxidation in situ and releases metabolites such as F4‐neuroprostane (4‐F4t‐NeuroP). The presence of 4‐F4t‐NeuroP in the brain is not well explored. In this study, 4‐F4t‐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‐F4t‐NeuroP. Additionally, 4‐F4t‐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‐F4t‐NeuroP is further oxidized. Our data suggest that 4‐F4t‐NeuroP could be neuroprotective in the native state but may have disadvantageous bioactivity when oxidized extensively.

Isoprostanoid Profiling of Marine Microalgae

“…Duda et al showed the role, also as lipid mediator, of some phytoprostanes in the immediate effector phase of allergic inflammation [38]. More recently, the work of Lee et al put forward the hypothesis of the neuroprotective effect of 4-F 4t -NeuroP in cellular and animal models [59]. Early studies on the cardiovascular system demonstrated that AA-oxidized derivatives induced platelet aggregation or showed a hypertensive effect [60,61].…”

Chemical Compositional Changes in Over-Oxidized Fish Oils

“…So far, the DHA-derived 4( RS )-4-F 4t -NeuroP is the most potent LCPUFA-derived isoprostanoid identified and possesses antiarrhythmic activities both in vivo and in vitro via the protection of the ryanodine receptor [ 89 ] and similarly protects against ventilator-induced diaphragmatic dysfunction in vivo [ 90 ]. Recently, Lee et al reported that 4( RS )-4-F 4t -NeuroP upregulates the transcriptional level of the antioxidant enzyme heme oxygenase-1 in SH-SY5Y cells and primary neuronal culture, confirming the bioactivity of this neuroprostane [ 91 ].…”

Moving forward with isoprostanes, neuroprostanes and phytoprostanes: where are we now?

“…Recently, our group showed infusion of 4-F 4t -NeuroP in the lateral tail vein of rodents displayed a fast uptake (30 s) in the liver and plasma while it took approximately 2 h in the brain. Importantly, 4-F 4t -NeuroP was able to pass the blood-brain barrier and mediate anti-inflammatory molecules derived from enzymatic oxidation of DHA [40]. Further, 4-F 4t -NeuroP stimulated antioxidant hemoxygenase-1 gene in neuronal cells and potentially posed to have a regulatory role for cell survival [40].…”

“…Importantly, 4-F 4t -NeuroP was able to pass the blood-brain barrier and mediate anti-inflammatory molecules derived from enzymatic oxidation of DHA [40]. Further, 4-F 4t -NeuroP stimulated antioxidant hemoxygenase-1 gene in neuronal cells and potentially posed to have a regulatory role for cell survival [40]. Some human and animal studies found NeuroPs, specifically 4-F 4t -NeuroP and 10-F 4t -NeuroP, were related to neurological disorders [32,41].…”

“…DHA is the most abundant ω-3 PUFA in humans and highly enriched in several tissues including the cerebral cortex and retina. F 4 -NeuroPs are widely used as biomarkers for oxidative damage related to the central nervous system [40]. Due to its high abundance, particularly in grey matter of the brain, elevation of F 4 -NeuroPs, especially 4-F 4t -NeuroP is considered a exclusive indicator for neuronal oxidative damage [42,45].…”