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Papers In Press, published online ahead of print July 19, 2002
Medicine and Pharmacology, Vanderbilt University Sch of Med, Nashville, TN 37232-6602
Corresponding Author: jason.morrow{at}mcmail.vanderbilt.edu
Free radical-initiated lipid peroxidation has been implicated in many neural disorders. Docosahexaenoic acid is the most abundant unsaturated fatty acid in the central nervous system. We have shown that this 22-carbon fatty acid can yield, upon oxidation, isoprostane-like compounds termed neuroprostanes, with E/D-type prostane rings (E4/D4-neuroprostanes). Eicosanoids with E/D-type prostane rings dehydrate to cyclopentenone-containing compounds possessing A-type and J-type prostane rings, respectively. We explored whether cyclopentenone neuroprostanes (A4/J4-neuroprostanes) are formed from the dehydration of E4/D4-neuroprostanes. Oxidation of docosahexaenoic acid in vitro increased levels of putative A4/J4-neuroprostanes 64-fold from 88 +/- 43 ng/mg of docosahexaenoic acid to 5463 +/- 2579 ng/mg of docosahexaenoic acid. Chemical approaches and liquid chromatography/electrospray ionization tandem mass spectrometry identified them as A4/J4-neuroprostanes. These compounds are formed in significant amounts from a biological source, rat brain synaptosomes. A4/J4-neuroprostanes increased 13-fold, from a basal level of 89 ± 72 ng/mg protein to 1187 ±217 ng/mg (n=4), upon oxidation. We detected these compounds in large amounts in fresh brain tissue from rats at levels of 97 +/- 25 ng/g brain tissue (n=3) and from humans at levels of 98 +/- 26 ng/g brain tissue (n=5), quantities that are an order of magnitude higher than other classes of neuroprostanes. Owing to the fact that A4/J4-neuroprostanes contain highly reactive cyclopentenone ring structures, it would be predicted that they undergo Michael addition with glutathione and adduct to proteins. Indeed, incubation of A4/J4-neuroprostanes in vitro with glutathione resulted in the formation of large amounts of adducts. These studies have identified novel, highly reactive A/J-ring isoprostane-like compounds derived from docosahexaenoic acid in vivo. The fact they are readily detectable in large quantities and are highly reactive provides a basis for exploring the role of these compounds in the pathogenesis of neurological disease associated with oxidant brain injury.
J. Biol. Chem, 10.1074/jbc.M205638200
Submitted on June 6, 2002
Revised on July 15, 2002
Accepted on July 19, 2002
Formation of highly reactive A-ring and J-ring isoprostane like compounds (A4/J4-neuroprostanes) In Vivo from docosahexaenoic acid
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