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J. Biol. Chem., Vol. 283, Issue 1, 6-16, January 4, 2008

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Neurofurans, Novel Indices of Oxidant Stress Derived from Docosahexaenoic Acid^*

Wen-Liang Song, John A. Lawson, Dermot Reilly, Joshua Rokach^¶, Chih-Tsung Chang^¶, Benoit Giasson, and Garret A. FitzGerald¹

From the Institute for Translational Medicine and Therapeutics and the Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the ^¶Claude Pepper Institute and the Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901

Isoeicosanoids are free radical-catalyzed isomers of the enzymatic products of arachidonic acid. They are formed in situ in cell membranes, are cleaved, circulate, and are excreted in urine. Isomers of prostaglandin F₂, the F₂-isoprostanes, have emerged as sensitive indices of lipid peroxidation in vivo. Analogous compounds formed from docosahexaenoic acid (DHA) are termed neuroprostanes and are more abundant than isoprostanes (iPs) in brain. Isofurans are another class of isoeicosanoids characterized by a substituted tetrahydrofuran ring. They are preferentially formed, relative to iPs, under conditions of elevated oxygen tension. Here, we report the discovery of neurofurans (nFs), the analogous family of compounds formed from DHA. Formation of nFs is characterized by mass spectrometry and confirmed by oxidation of DHA in vitro and following CCl₄ administration in liver in vivo. It is demonstrated that the levels of nFs are elevated in the brain cortex of a mouse model of Alzheimer disease and are depressed in mouse brain cortex by deletion of p47^phox, an essential component of the phagocyte NADPH oxidase. Measurement of the nFs may ultimately prove useful in diagnosis, timing, and selection of dose in the treatment and chemoprevention of neurodegenerative disease.

Received for publication, July 25, 2007 , and in revised form, October 2, 2007.

^* This work was supported by National Institutes of Health Grants HL62250 (to G. A. F.) and HL-81873 (to J. R.). This work was also supported in part by National Science Foundation Grants AMX-360 CHE-90-13145 and CHE-03-42251 (to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ McNeil Professor of Translational Medicine and Therapeutics. To whom correspondence should be addressed: 153 Johnson Pavilion, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. Tel.: 215-898-1184; Fax: 215-573-9135; E-mail: garret{at}spirit.gcrc.upenn.edu.

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