Formation of Novel D-Ring and E-Ring Isoprostane-like Compounds (D4/E4-Neuroprostanes) in Vivo from Docosahexaenoic Acid

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• 作者：Erin E. Reich ; William E. Zackert ; Cynthia J. Brame ; Yan Chen ; L. Jackson Roberts ; II ; David L. Hachey ; Thomas J. Montine ; and Jason D. Morrow
• 刊名：Biochemistry
• 出版年：2000
• 出版时间：March 7, 2000
• 年：2000
• 卷：39
• 期：9
• 页码：2376 - 2383
• 全文大小：225K
• 年卷期：v.39,no.9(March 7, 2000)
• ISSN：1520-4995

文摘

Free radical-mediated oxidant injury and lipid peroxidation have been implicated in a numberof neural disorders. We have reported that bioactive prostaglandin D₂/E₂-like compounds, termed D₂/E₂-isoprostanes, are produced in vivo by the free radical-catalyzed peroxidation of arachidonic acid.Docosahexaenoic acid, in contrast to arachidonic acid, is the most abundant unsaturated fatty acid inbrain. We therefore questioned whether D/E-isoprostane-like compounds (D₄/E₄-neuroprostanes) are formedfrom the oxidation of docosahexaenoic acid. Levels of putative D₄/E₄-neuroprostanes increased 380-foldafter oxidation of docosahexaenoic acid in vitro from 15.2 ± 6.3 to 5773 ± 1024 ng/mg of docosahexaenoicacid. Subsequently, chemical approaches and liquid chromatography electrospray ionization tandem massspectrometry definitively identified these compounds as D₄/E₄-neuroprostanes. We then explored theformation of D₄/E₄-neuroprostanes from a biological source, rat brain synaptosomes. Basal levels of D₄/E₄-neuroprostanes were 3.8 ± 0.6 ng/mg of protein and increased 54-fold after oxidation (n = 4). Wealso detected these compounds in fresh brain tissue from rats at levels of 12.1 ± 2.4 ng/g of brain tissue(n = 3) and in human brain tissue at levels of 9.2 ± 4.1 ng/g of brain tissue (n = 4). Thus, these studieshave identified novel D/E-ring isoprostane-like compounds that are derived from docosahexaenoic acidand that are formed in brain in vivo. The fact that they are readily detectable suggests that ongoing oxidativestress is present in the central nervous system of humans and animals. Further, identification of thesecompounds provides a rationale for examining their role in neurological disorders associated with oxidantstress.