The lipid peroxidation product 4-hydroxy-2,3-nonenal inhibits constitutive and inducible activity of nuclear factor kappa B in neurons.
Peroxidation of membrane lipids occurs in many different neurodegenerative conditions including stroke, and Alzheimer's and Parkinson's diseases. Recent findings suggest that lipid peroxidation can promote neuronal death by a mechanism involving production of the toxic aldehyde 4-hydroxy-2,3-nonenal (HNE), which may act by covalently modifying proteins and impairing their function. The transcription factor NF-kappa B can prevent neuronal death in experimental models of neurodegenerative disorders by inducing the expression of anti-apoptotic proteins including Bcl-2 and manganese superoxide dismutase. We now report that HNE selectively suppresses basal and inducible NF-kappa B DNA binding activity in cultured rat cortical neurons. Immunoprecipitation-immunoblot analyses using antibodies against HNE-conjugated proteins and p50 and p65 NF-kappa B subunits indicate that HNE does not directly modify NF-kappa B proteins. Moreover, HNE did not affect NF-kappa B DNA-binding activity when added directly to cytosolic extracts, suggesting that HNE inhibits an upstream component of the NF-kappa B signaling pathway. Inhibition of the survival-promoting NF-kappa B signaling pathway by HNE may contribute to neuronal death under conditions in which membrane lipid peroxidation occurs.
Camandola
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S
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center 4F02, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Poli
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Mattson
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D000447:Aldehydes / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D020521:Stroke / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D018808:Transcription Factor AP-1; C076715:pervanadate; D019319:Okadaic Acid; D014638:Vanadates; D003513:Cycloheximide; C027576:4-hydroxy-2-nonenal