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M706124200v1
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Papers In Press, published online ahead of print October 6, 2007
J. Biol. Chem, 10.1074/jbc.M706124200
Submitted on July 25, 2007
Revised on October 2, 2007
Accepted on October 6, 2007

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. FitzGerald

Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104

Corresponding Author: garret{at}spirit.gcrc.upenn.edu

Isoeicosanoids are free radical catalyzed isomers of the enzymatic products of arachidonic acid (AA). They are formed in situ in cell membranes, are cleaved, circulate and are excreted in urine. Isomers of prostaglandin F2a – the F2-isoprostanes (iPs) have emerged as sensitive indices of lipid peroxidation in vivo. Analogous compounds formed from docosahexaenoic acid (DHA) are termed neuroprostanes (nPs) and are more abundant than iPs in brain. Isofurans (iFs) 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 the brain cortex by deletion of p47phox, 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.


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