title: Trans-4-hydroxy-2-hexenal is a neurotoxic product of docosahexaenoic (22:6; n-3) acid oxidation.
abstract: Lipid peroxidation of docosahexaenoic (22:6; n-3) acid (DHA) is elevated in the CNS in patients with Alzheimer's disease and in animal models of seizure and ethanol withdrawal. One product of DHA oxidation is trans-4-hydroxy-2-hexenal (HHE), a six carbon analog of the n-6 fatty acid derived trans-4-hydroxy-2-nonenal (HNE). In this work, we studied the neurotoxic potential of HHE. HHE and HNE were toxic to primary cultures of cerebral cortical neurons with LD(50)'s of 23 and 18 micromol/L, respectively. Toxicity was prevented by the addition of thiol scavengers. HHE and HNE depleted neuronal GSH content identically with depletion observed with 10 micromol/L of either compound. Using an antibody raised against HHE-protein adducts, we show that HHE modified specific proteins of 75, 50, and 45 kDa in concentration- and time-dependent manners. The time-dependent formation of HHE differed from that of F4-neuroprostanes following in vitro DHA oxidation likely as a result of the different oxidation pathways involved. Using purified mitochondrial aldehyde dehydrogenase ALDH5A, we found that HHE was oxidized 6.5-fold less efficiently than HNE. Our data demonstrate that HHE and HNE have similarities but also differences in their neurotoxic mechanisms and metabolism.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, Grand Forks, North Dakota 58203, USA.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Long
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Murphy
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Leiphon
authors.forename: John
authors.initials: J
authors.lastname: Watt
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Jocelyn R H
authors.initials: JR
authors.lastname: Howard
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Picklo
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D020208:Brain Injury, Chronic / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D050644:Succinate-Semialdehyde Dehydrogenase / Q000378:metabolism; D013997:Time Factors
chemical_list: D000447:Aldehydes; D016166:Free Radical Scavengers; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; C045934:4-hydroxy-2-hexenal; D004281:Docosahexaenoic Acids; C493647:Aldh5a1 protein, rat; D050644:Succinate-Semialdehyde Dehydrogenase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal