4-hydroxy-2-nonenal and ferrous-chloride

Oxygenation of the 5-lipoxygenase product 5S-hydroxyeicosatetraenoic acid by cyclooxygenase-2 yields a bicyclic di-endoperoxide. The di-endoperoxide contains two peroxides spanning from carbons 9 to 11 and 8 to 12, and two hydroxyls at carbons 5 and 15 of arachidonic acid (Schneider C., et al. 2006. Convergent oxygenation of arachidonic acid by 5-lipoxygenase and cyclooxygenase-2. J. Am. Chem. Soc. 128: 720). Here, we report that treatment of the di-endoperoxide with hematin or ferrous chloride results in cleavage of both peroxide O-O bonds and of the bonds between the carbons that carry the peroxide groups, producing the aldehydes 4-hydroxy-2E-nonenal (4-HNE), 8-oxo-5S-hydroxy-6E-octenoic acid, and malondialdehyde (MDA). The hematin- and ferrous iron-catalyzed transformation of the di-endoperoxide proceeded with a similar yield of products as the cleavage of the prostaglandin endoperoxide PGH(2) to 12S-hydroxy-5Z,8E,10E-heptadecatrienoic acid and MDA. Chiral phase HPLC analysis of the 4-HNE cleavage product showed greater than 98% 4S and thus established the S configuration of the 15-carbon of the di-endoperoxide that had not previously been assigned. This transformation of the 5-lipoxygenase/cyclooxygenase-2 derived di-endoperoxide invokes the possibility of a novel pathway to formation of the classic lipid peroxidation products 4-HNE and MDA.

Topics: Aldehydes; Arachidonate 5-Lipoxygenase; Biocatalysis; Cyclooxygenase 2; Ferrous Compounds; Heme; Hemin; Hydroxyeicosatetraenoic Acids; Malondialdehyde; Peroxides; Stereoisomerism

The mechanisms that underlie cholinergic neuronal degeneration in Alzheimer disease (AD) are unclear, but recent data suggest that oxidative stress plays a role. We report that 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, damages and kills basal forebrain cholinergic neurons when administered intraparenchymally. Examination of Nissl-stained brain sections following unilateral HNE infusion revealed widespread neuronal loss in basal forebrain ipsilateral to the injection, but not on the contralateral side. Levels of choline acetyltransferase activity and immunoreactivity in the ipsilateral basal forebrain and hippocampus were significantly reduced by 60-80% seven days following HNE administration. Performance in Morris water maze tasks of visuospatial memory was severely impaired in a dose-dependent manner seven days following bilateral administration of HNE. Bilateral infusion of FeCl2 (an inducer of membrane lipid peroxidation) into the basal forebrain caused neuron loss and decreased choline acetyltransferease immunoreactivity and deficits in visuospatial memory. Additionally, FeCl2 infusion increased HNE immunoreactivity, implicating HNE in iron-induced oxidative damage. Because recent studies have demonstrated HNE adducts in degenerating neurons in AD brain, the present findings suggest a role for HNE in damage to cholinergic neurons in AD.

Topics: Aldehydes; Animals; Behavior, Animal; Choline O-Acetyltransferase; Cholinergic Fibers; Ferrous Compounds; Hippocampus; Injections, Intraventricular; Lipid Peroxidation; Male; Maze Learning; Memory; Neurons; Prosencephalon; Rats; Rats, Sprague-Dawley; Space Perception