title: Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid.
abstract: F2-isoprostanes are prostaglandin F2-like compounds that are formed nonenzymatically by free radical-induced oxidation of arachidonic acid. We explored whether oxidation of docosahexaenoic acid (C22:6omega3), which is highly enriched in the brain, led to the formation of F2-isoprostane-like compounds, which we term F4-neuroprostanes. Oxidation of docosahexaenoic acid in vitro yielded a series of compounds that were structurally established to be F4-neuroprostanes using a number of mass spectrometric approaches. The amounts formed exceeded levels of F2-isoprostanes generated from arachidonic acid by 3.4-fold. F4-neuroprostanes were detected esterified in normal whole rat brain and newborn pig cortex at a level of 7.0 +/- 1.4 ng/g and 13.1 +/- 8 ng/g, respectively. Furthermore, F4-neuroprostanes could be detected in normal human cerebrospinal fluid and levels in patients with Alzheimer's disease (110 +/- 12 pg/ml) were significantly higher than age-matched controls (64 +/- 8 pg/ml) (p < 0.05). F4-neuroprostanes may provide a unique marker of oxidative injury to the brain and could potentially exert biological activity. Furthermore, the formation of F4-neuroprostane-containing aminophospholipids might adversely effect neuronal function as a result of alterations they induce in the biophysical properties of neuronal membranes.
authors.affiliation: Departments of Pharmacology, Pathology, and Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA. jack.roberts@mcmail.vanderbilt.edu
authors.forename: L J
authors.initials: LJ
authors.lastname: Roberts
authors.forename: T J
authors.initials: TJ
authors.lastname: Montine
authors.forename: W R
authors.initials: WR
authors.lastname: Markesbery
authors.forename: A R
authors.initials: AR
authors.lastname: Tapper
authors.forename: P
authors.initials: P
authors.lastname: Hardy
authors.forename: S
authors.initials: S
authors.lastname: Chemtob
authors.forename: W D
authors.initials: WD
authors.lastname: Dettbarn
authors.forename: J D
authors.initials: JD
authors.lastname: Morrow
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid; D000818:Animals; D001921:Brain / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000134:cerebrospinal fluid; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D051381:Rats; D013237:Stereoisomerism; D013552:Swine
chemical_list: D004281:Docosahexaenoic Acids; D015237:Dinoprost