Brand_2008_J.Neurochem_105_1325

Iron, a transition metal and essential nutrient, is a typical pro-oxidant forming free radicals, lipid peroxides and causing cell damage when added at high (> or = 50 microM) concentrations to oligodendroglia-like OLN-93 cells that have been enriched for 3 days with 10 microM docosahexaenoic acid (DHA, 22 : 6 n-3). At low (5 microM) iron concentrations lipid peroxides were still formed, but cells turned resistant to 250 microM H2O2, a secondary genotoxic stress. This has been attributed most likely to a time-dependent (16 h preconditioning) increase of cellular antioxidant enzyme activities i.e., glutathione peroxidase (38%) and glutathione reductase (26%). DHA but not arachidonic acid (20 : 4 n-6) supplements induced 3-fold increase in gene expression of divalent metal transporter-1, a transporter protein presumably responsible for the increase in intracellular iron. Elevated iron levels triggered a transient scrambling of membrane lipid asymmetry as evident by an accelerated ethanolamine phosphoglyceride translocation to the outer cell surface. Ethanolamine phosphoglyceride reorientation is proposed to activate certain signaling cascades leading to changes in nuclear transcription, a reaction that could represent a mechanism of preconditioning. These findings may have important implications for understanding the interactive role of iron and DHA in nutritional deficiencies, losses of polyunsaturated fatty acids in the aging brain or excessive iron accumulation in degenerative disorders.