The lipid peroxidation product 4-hydroxy-2,3-nonenal inhibits constitutiveand 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. Rece nt 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-kappaB can prevent neuronal death in experimental models of neurodegenerative disorders by inducing the expressi on of anti-apoptotic proteins including Bcl-2 and manganese superoxide dism utase. We now report that HNE selectively suppresses basal and inducible NF -kappaB DNA binding activity in cultured rat cortical neurons. Immunoprecip itation-immunoblot analyses using antibodies against HNE-conjugated protein s and p50 and p65 NF-kappaB subunits indicate that HNE does not directly mo dify NF-kappaB proteins. Moreover, HNE did not affect NF-kappaB DNA-binding activity when added directly to cytosolic extracts, suggesting that HNE in hibits an upstream component of the NF-kappaB signaling pathway. Inhibition of the survival-promoting NF-kappaB signaling pathway by HNE may contribut e to neuronal death under conditions in which membrane lipid peroxidation o ccurs. (C) 2000 Elsevier Science BN. All rights reserved.