Neurofurans, novel indices of oxidant stress derived from docosahexaenoic acid.
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 F(2alpha), the F(2)-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 CCl(4) 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.
Song
Wen-Liang
WL
Institute for Translational Medicine and Therapeutics and the Philadelphia, Pennsylvania 19104; Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the.
Lawson
John A
JA
Institute for Translational Medicine and Therapeutics and the Philadelphia, Pennsylvania 19104; Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the.
Reilly
Dermot
D
Institute for Translational Medicine and Therapeutics and the Philadelphia, Pennsylvania 19104; Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the.
Rokach
Joshua
J
Claude Pepper Institute and the Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901.
Chang
Chih-Tsung
CT
Claude Pepper Institute and the Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901.
Giasson
Benoit
B
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the.
FitzGerald
Garret A
GA
Institute for Translational Medicine and Therapeutics and the Philadelphia, Pennsylvania 19104; Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the. Electronic address: garret@spirit.gcrc.upenn.edu.
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D002853:Chromatography, Liquid; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism*; D005663:Furans / Q000737:chemistry / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D028421:Isoprostanes / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D015394:Molecular Structure; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D005663:Furans; D028421:Isoprostanes; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D002251:Carbon Tetrachloride