The lipid peroxidation product 4-hydroxy-2,3-nonenal inhibits constitutive and inducible activity of nuclear factor kappa B in neurons

Brain Res Mol Brain Res. 2000 Dec 28;85(1-2):53-60. doi: 10.1016/s0169-328x(00)00234-5.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldehydes / pharmacology*
  • Alzheimer Disease / metabolism
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Cycloheximide / pharmacology
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Lipid Peroxidation / physiology*
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Nerve Degeneration / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Okadaic Acid / pharmacology
  • Protein Synthesis Inhibitors / pharmacology
  • Rats
  • Stroke / metabolism
  • Transcription Factor AP-1 / metabolism
  • Vanadates / pharmacology

Substances

  • Aldehydes
  • Cysteine Proteinase Inhibitors
  • Enzyme Inhibitors
  • NF-kappa B
  • Protein Synthesis Inhibitors
  • Transcription Factor AP-1
  • pervanadate
  • Okadaic Acid
  • Vanadates
  • Cycloheximide
  • 4-hydroxy-2-nonenal