FORMATION OF ISOPROSTANE-LIKE COMPOUNDS (NEUROPROSTANES) IN-VIVO FROMDOCOSAHEXAENOIC ACID

F-2-isoprostanes are prostaglandin F-2-like compounds that are formed nonenzymatically by free radical-induced oxidation of arachidonic acid . We explored whether oxidation of docosahexaenoic acid (C22:6 omega 3 ), which is highly enriched in the brain, led to the formation of F-2- isoprostane-like compounds, which we term F-4-neuroprostanes. Oxidatio n of docosahexaenoic acid in vitro yielded a series of compounds that were structurally established to be F-4-neuroprostanes using a number of mass spectrometric approaches. The amounts formed exceeded levels o f F-2-isoprostanes generated from arachidonic acid by 3.4-fold. F-4-ne uroprostanes were detected esterified in normal whole rat brain and ne wborn pig cortex at a level of 7.0 +/- 1.4 ng/g and 13.1 +/- 8 ng/g, r espectively. Furthermore, F-4-neuroprostanes could be detected in norm al human cerebrospinal fluid and levels in patients with Alzheimer's d isease (110 +/- 12 pg/ml) were significantly higher than age-matched c ontrols (64 +/- 8 pg/ml) (p < 0.05), F-4-neuroprostanes may provide a unique marker of oxidative injury to the brain and could potentially e xert biological activity. Furthermore, the formation of F-4-neuroprost ane-containing aminophospholipids might adversely effect neuronal func tion as a result of alterations they induce in the biophysical propert ies of neuronal membranes.