Cyclopentenone isoprostanes are novel bioactive products of lipid oxidation which enhance neurodegeneration.
Oxidative stress and subsequent lipid peroxidation are involved in the pathogenesis of numerous neurodegenerative conditions, including stroke. Cyclopentenone isoprostanes (IsoPs) are novel electrophilic lipid peroxidation products formed under conditions of oxidative stress via the isoprostane pathway. These cyclopentenone IsoPs are isomeric to highly bioactive cyclopentenone prostaglandins, yet it has not been determined if these products are biologically active or are formed in the brain. Here we demonstrate that the major cyclopentenone IsoP isomer 15-A2t-IsoP potently induces apoptosis in neuronal cultures at submicromolar concentrations. We present a model in which 15-A2t-IsoP induced neuronal apoptosis involves initial depletion of glutathione and enhanced production of reactive oxygen species, followed by 12-lipoxygenase activation and phosphorylation of extracellular signal-regulated kinase 1/2 and the redox sensitive adaptor protein p66shc, which results in caspase-3 cleavage. 15-A2t-IsoP application also dramatically potentiates oxidative glutamate toxicity at concentrations as low as 100 nm, demonstrating the functional importance of these molecules in neurodegeneration. Finally, we employ novel mass spectrometric methods to show that cyclopentenone IsoPs are formed abundantly in brain tissue under conditions of oxidative stress. Together these findings suggest that cyclopentenone IsoPs may contribute to neuronal death caused by oxidative insults, and that their activity should perhaps be addressed when designing neuroprotective therapies.
Musiek
Erik S
ES
Department of Pharmacology, Venderbilt University, Nashville, Tennessee 37232, USA.
Breeding
Rebecca S
RS
Milne
Ginger L
GL
Zanoni
Giuseppe
G
Morrow
Jason D
JD
McLaughlin
Bethann
B
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D005978:Glutathione / Q000172:deficiency; D028421:Isoprostanes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008959:Models, Neurological; D015394:Molecular Structure; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011454:Prostaglandins A / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
C117466:8-isoprostaglandin A2; D048868:Adaptor Proteins, Signal Transducing; D003517:Cyclopentanes; D018690:Excitatory Amino Acid Agonists; D028421:Isoprostanes; D011454:Prostaglandins A; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018698:Glutamic Acid; D001092:Arachidonate 12-Lipoxygenase; D048052:Mitogen-Activated Protein Kinase 3; D005978:Glutathione; C013905:cyclopentenone