Simvastatin prevents oxygen and glucose deprivation/reoxygenation-induced death of cortical neurons by reducing the production and toxicity of 4-hydroxy-2 E-nonenal.

Ji Hyae Lim; Jae-Chul Lee; Yong Hyun Lee; In Young Choi; Yu-Kyoung Oh; Hee-Sun Kim; Jin-Sun Park; Won-Ki Kim

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-2 E-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-κB), and the cytotoxicity of HNE was in good correlation with inactivation of NF-κB. Simvastatin reversed the inhibition of NF-κB activity induced by OGD/reoxygenation or HNE. The neuroprotection by simvastatin was significantly attenuated by various NF-κB inhibitors, implying that simvastatin inhibits the cytotoxicity of HNE at least in part by maintaining the activity of NF-κB. Further understanding of the neuroprotective mechanism of simvastatin may provide a therapeutic strategy for oxidative stress-related neurodegenerative diseases.

STATINS (Cardiovascular agents); NEURONS; OXYGEN; METHYL aspartate; NF-kappa B; OXIDATIVE stress

Journal of Neurochemistry, 2006, Vol 97, Issue 1, p140

0022-3042

Academic Journal

10.1111/j.1471-4159.2006.03715.x