EVIDENCE THAT 4-HYDROXYNONENAL MEDIATES OXIDATIVE STRESS-INDUCED NEURONAL APOPTOSIS

Oxidative stress is believed to play important roles in neuronal cell death associated with many different neurodegenerative conditions (e.g ., Alzheimer's disease, Parkinson's disease, and cerebral ischemia), a nd it is believed also that apoptosis is an important mode of cell dea th in these disorders. Membrane lipid peroxidation has been documented in the brain regions affected in these disorders as well as in cell c ulture and in vivo models. We now provide evidence that 4-hydroxynonen al (HNE), an aldehydic product of membrane lipid peroxidation, is a ke y mediator of neuronal apoptosis induced by oxidative stress. HNE indu ced apoptosis in PC12 cells and primary rat hippocampal neurons. Oxida tive insults (FeSO4 and amyloid beta-peptide) induced lipid peroxidati on, cellular accumulation of HNE, and apoptosis. Bcl-2 prevented apopt osis of PC12 cells induced by oxidative stress and HNE. Antioxidants t hat suppress lipid peroxidation protected against apoptosis induced by oxidative insults, but not that induced by HNE. Glutathione, which bi nds HNE, protected neurons against apoptosis induced by oxidative stre ss and HNE. PC12 cells expressing Bcl-2 exhibited higher levels of glu tathione and lower levels of HNE after oxidative stress. Collectively, the data identify that HNE is a novel nonprotein mediator of oxidativ e stress-induced neuronal apoptosis and suggest that the antiapoptotic action of glutathione may involve detoxification of HNE.