Abstract
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.
Highlights
Urine as indices of in vivo lipid peroxidation [2]
Neuroprostanes are iPs derived from the -3 fatty acid, docosahexaenoic acid (DHA) [3]
Selected ion monitoring (SIM) analysis of m/z 393 revealed a region of incompletely resolved chromatographic peaks that eluted slightly earlier than the iPs, nPs, and iFs in a reverse phase LC gradient (Fig. 2a)
Summary
Treatment of mice with CCl4 was used to induce oxidant injury to the liver as previously described [8]. The mice were anesthetized with CO2 prior to sacrifice at 0, 1, 2.5, 7.5, and 20 h after CCl4 administration, and their livers were removed and rapidly frozen in liquid nitrogen prior to storage at Ϫ80 °C. Frozen samples (0.1– 0.5g) were suspended in 5 ml of ice-cold chloroform: methanol (2:1, v/v) with 0.005% (w/v) butylated hydroxytoluene to suppress oxidation. The lipid extracts were mixed vigorously with 2.0 ml NaCl (0.9%, w/v), and the phases were separated by centrifugation. After the upper phase was decanted, the samples were transferred to clean tubes, and the residual organic solvent was removed under a stream of nitrogen. Lipid extracts were saponified by adding 0.5 ml of 2.7 N KOH in 0.5 ml of methanol
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