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Originally published In Press as doi:10.1074/jbc.M205638200 on July 19, 2002

J. Biol. Chem., Vol. 277, Issue 39, 36076-36084, September 27, 2002
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Formation of Highly Reactive A-ring and J-ring Isoprostane-like Compounds (A4/J4-neuroprostanes) in Vivo from Docosahexaenoic Acid*

Samuel S. Fam, Laine J. Murphey, Erin S. Terry, William E. Zackert, Yan Chen, Ling Gao, Saurabh Pandalai, Ginger L. Milne, L. Jackson Roberts, Ned A. Porter, Thomas J. Montine, and Jason D. MorrowDagger

From the Departments of Medicine, Pharmacology, Chemistry, and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Free radical-initiated oxidant injury and lipid peroxidation have been implicated in a number of neural disorders. Docosahexaenoic acid is the most abundant unsaturated fatty acid in the central nervous system. We have shown previously 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 are unstable and dehydrate to cyclopentenone-containing compounds possessing A-type and J-type prostane rings, respectively. We thus explored whether cyclopentenone neuroprostanes (A4/J4-neuroprostanes) are formed from the dehydration of E4/D4-neuroprostanes. Indeed, oxidation of docosahexaenoic acid in vitro increased levels of putative A4/J4-neuroprostanes 64-fold from 88 ± 43 to 5463 ± 2579 ng/mg docosahexaenoic acid. Chemical approaches and liquid chromatography/electrospray ionization tandem mass spectrometry definitively identified them as A4/J4-neuroprostanes. We subsequently showed 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 also detected these compounds in very 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 nearly an order of magnitude higher than other classes of neuroprostanes. Because of the fact that A4/J4-neuroprostanes contain highly reactive cyclopentenone ring structures, it would be predicted that they readily undergo Michael addition with glutathione and adduct covalently to proteins. Indeed, incubation of A4/J4-neuroprostanes in vitro with excess glutathione resulted in the formation of large amounts of adducts. Thus, these studies have identified novel, highly reactive A/J-ring isoprostane-like compounds that are derived from docosahexaenoic acid in vivo.

* This work was supported in part by National Institutes of Health Grants DK48831, GM15431, CA77839, GM42056, GM07569, AG16835, and AG05144.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. To whom correspondence should be addressed: 526 RRB, Vanderbilt University School of Medicine, Nashville, TN 37232-6602. Tel.: 615-343-1124; Fax: 615-322-3669; E-mail: jason.morrow@mcmail.vanderbilt.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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