title: Simvastatin prevents oxygen and glucose deprivation/reoxygenation-induced death of cortical neurons by reducing the production and toxicity of 4-hydroxy-2E-nonenal.
abstract: Lipid membrane peroxidation is highly associated with neuronal death in various neurodegenerative diseases including cerebral stroke. Here, we report that simvastatin decreases oxygen and glucose deprivation (OGD)/reoxygenation-evoked neuronal death by inhibiting the production and cytoxicity of 4-hydroxy-2E-nonenal (HNE), the final product of lipid peroxidation. Simvastatin markedly decreased the OGD/reoxygenation-evoked death of cortical neurons. OGD/reoxygenation increased the intracellular HNE level mostly in neuronal cells, not glial cells. Simvastatin decreased the intracellular level of HNE in neuronal cells exposed to OGD/reoxygenation. We further found that HNE induced the cytotoxicity in neuronal cells and synergistically increased the N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. Simvastatin largely blocked the NMDA neurotoxicity potentiated by HNE. However, simvastatin did not alter the NMDA-evoked calcium influx in the absence or presence of HNE. HNE inhibited the activity of nuclear factor-kappa B (NF-kappaB), and the cytotoxicity of HNE was in good correlation with inactivation of NF-kappaB. Simvastatin reversed the inhibition of NF-kappaB activity induced by OGD/reoxygenation or HNE. The neuroprotection by simvastatin was significantly attenuated by various NF-kappaB inhibitors, implying that simvastatin inhibits the cytotoxicity of HNE at least in part by maintaining the activity of NF-kappaB. Further understanding of the neuroprotective mechanism of simvastatin may provide a therapeutic strategy for oxidative stress-related neurodegenerative diseases.
authors.affiliation: Department of Neuroscience, College of Medicine, Laboratory of neurodegenerative diseases, Ewha Medical Center, Ewha Women's University, Seoul, Korea.
authors.forename: Ji Hyae
authors.initials: JH
authors.lastname: Lim
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Lee
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Lee
authors.forename: In Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D019821:Simvastatin; C027576:4-hydroxy-2-nonenal