MYELIN IS A PREFERENTIAL TARGET OF ALUMINUM-MEDIATED OXIDATIVE DAMAGE

The capacity of Al3+ to promote oxidative damage to brain membranes wa s investigated both in vitro and in vivo. In vitro, Al3+ and related m etals (Sc3+, Ga3+, In3+, Be2+, Y3+, and La3+) stimulated Fe2+-initiate d lipid and protein oxidation in brain myelin and synaptic membranes. Al3+, Sc3+, Y3+, and La3+ significantly promoted protein-associated ca rbonyl production in myelin, while in synaptic membranes, the stimulat ory effect was observed in the presence of Ga3+, In3+, Y3+, Sc3+, and La3+. In myelin the magnitude of the stimulation of lipid oxidation fo llowed the order Sc3+, Y3+, La3+ > Al3+, Ga3+, In3+ > Be2+. When compa red to mitochondria and microsomal and synaptic membranes, myelin show ed a marked susceptibility to Al3+-mediated lipid peroxidation. The di fferential susceptibility of myelin compared to synaptic membranes cou ld not be explained by differences in membrane composition, since the relative content of negatively charged phospholipids (binding sites) w as similar for both membranes, and myelin had a lower content of poly- unsaturated fatty acids (substrates of lipid oxidation) and a higher c oncentration of alpha-tocopherol compared to synaptic membranes. In a model of Al3+ intoxication imposed to mice during pregnancy and early development, a 72% higher content of lipid peroxidation products was f ound in brain myelin. The fluidity of myelin evaluated by the polariza tion fluorescence of 1,3-diphenylhexatriene was significantly higher i n the Al3+-intoxicated mice than in controls. Since myelin has a high relative content of lipid:protein compared to other membranes, these r esults support our hypothesis that ions without redox capacity can sti mulate in vitro and in vivo lipid oxidation by promoting phase separat ion and membrane rigidification, thus accelerating lipid oxidation. (C ) 1997 Academic Press.