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Journal of Lipid Research, Vol. 49, 995-1005, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

F₂-Dihomo-isoprostanes arise from free radical attack on adrenic acid^*

Mike VanRollins^*, Randall L. Woltjer^*, Huiyong Yin, Jason D. Morrow and Thomas J. Montine^1,*

^* Department of Pathology, University of Washington, Seattle, WA
Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN

^* This work was supported by National Institutes of Health Grants AG-24011, AG-05136, AG-23801, DK-48831, CA-77839, GM-15431, ES-13125, and NS-48595 and by the Nancy and Buster Alvord Endowment.

Published, JLR Papers in Press, February 5, 2008.

¹ To whom correspondence should be addressed. e-mail: tmontine{at}u.washington.edu

Unlike F₄-neuroprostanes (F₄-NeuroPs), which are relatively selective in vivo markers of oxidative damage to neuronal membranes, there currently is no method to assess the extent of free radical damage to myelin with relative selectively. The polyunsaturated fatty acid adrenic acid (AdA) is susceptible to free radical attack and, at least in primates, is concentrated in myelin within white matter. Here, we characterized oxidation products of AdA as potential markers of free radical damage to myelin in human brain. Unesterified AdA was reacted with a free radical initiator to yield products (F₂-dihomo-IsoPs) that were 28 Da larger than but otherwise closely resembled F₂-isoprostanes (F₂-IsoPs), which are generated by free radical attack on arachidonic acid. Phospholipids derived from human cerebral gray matter, white matter, and myelin similarly oxidized ex vivo showed that the ratio of esterified F₂-dihomo-IsoPs to F₄-NeuroPs was 10-fold greater in myelin-derived than in gray matter-derived phospholipids. Finally, we showed that F₂-dihomo-IsoPs are significantly increased in white matter samples from patients with Alzheimer's disease. We propose that F₂-dihomo-IsoPs may serve as quantitative in vivo biomarkers of free radical damage to myelin from primate white matter.

Supplementary key words damage • myelin • Alzheimer's disease • brain lipids

Abbreviations: AA, arachidonic acid; AAPH, 2,2'-azo-bis(2-methylpropionamidine)dihydrochloride; AD, Alzheimer's disease; AdA, adrenic acid; BSTFA, N,O-bis(trimethylsilyl)trifluoroacetamide; CID, collision-induced dissociation; DHA, docosahexaenoic acid; F₂-IsoP, F₂-isoprostane; F₄-NeuroP, F₄-neuroprostane; NICI-GC-MS, negative ion chemical ionization gas chromatography-mass spectrometry; SRM, selective reaction monitoring

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