Simvastatin Prevents Oxygen and Glucose deprivation/reoxygenation-induced Death of Cortical Neurons by Reducing the Production and Toxicity of 4-hydroxy-2E-nonenal

J Neurochem. 2006 Apr;97(1):140-50. doi: 10.1111/j.1471-4159.2006.03715.x. Epub 2006 Mar 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism*
  • Aldehydes / toxicity
  • Animals
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Cerebral Cortex
  • Cytoprotection / drug effects
  • Cytoprotection / physiology
  • Enzyme Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hypoxia-Ischemia, Brain / drug therapy
  • Hypoxia-Ischemia, Brain / metabolism*
  • Hypoxia-Ischemia, Brain / pathology
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / physiology
  • NF-kappa B / agonists
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Nerve Degeneration / prevention & control*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Neurotoxins / antagonists & inhibitors
  • Neurotoxins / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Simvastatin / pharmacology*

Substances

  • Aldehydes
  • Enzyme Inhibitors
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • NF-kappa B
  • Neuroprotective Agents
  • Neurotoxins
  • Receptors, N-Methyl-D-Aspartate
  • Simvastatin
  • 4-hydroxy-2-nonenal