Characterization of the molecular events following impairment of NF-kappaB-driven transcription in neurons

Brain Res Mol Brain Res. 2002 Dec 30;109(1-2):179-88. doi: 10.1016/s0169-328x(02)00558-2.

Abstract

Nuclear factor-kappaB (NF-kappaB) is a transcription factor with a pivotal role in neuronal homeostasis. Indeed, NF-kappaB trans-activates several antiapoptotic genes in neurons and inhibition of NF-kappaB transcriptional activity triggers neuronal apoptosis. However, the exact mechanisms by which neurons undergo apoptosis in conditions of NF-kappaB inhibition are poorly understood. To further clarify how NF-kappaB operates in neurons, and to gather information on the molecular events occurring during NF-kappaB inhibition-dependent neuronal apoptosis, this study evaluated the effects of recently identified NF-kappaB inhibitors such as parthenolide, SN50, BAY 11-7082 and helenalin on primary cultures of rat cortical neurons. Data show that NF-kappaB was constitutively activated in neurons, and demonstrate for the first time that drug-dependent NF-kappaB inhibition induced rapid mitochondrial release of cytochrome c, caspase-9 and -3 activation, poly(ADP-ribose) polymerase-1 cleavage, membrane blebbing and nuclear fragmentation, without evidence of procaspase-8 and Bid processing. Interestingly, a burst of Akt activation occurred in neurons exposed to NF-kappaB inhibitors. These events were preceded by selective reduction of mRNAs of NF-kappaB-dependent, antiapoptotic Bcl-2 family members such as Bcl-x(L), Bcl-2 and, in particular, A1/Bfl-1. The present study reports a novel, detailed temporal analysis of the molecular events following impairment of NF-kappaB-driven transcription in neurons and demonstrates that inhibition of constitutive neuronal NF-kappaB activity triggers selective activation of the intrinsic apoptotic program.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / physiology
  • Caspases / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Cytochrome c Group / metabolism
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Homeostasis / physiology*
  • Mitochondria / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Nitriles*
  • Organic Chemicals*
  • Peptides / chemistry
  • Peptides / pharmacology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Protein Binding
  • Protein Precursors / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Replication Protein C
  • Sesquiterpenes / pharmacology
  • Sesquiterpenes, Guaiane
  • Sulfones*
  • Transcription, Genetic*

Substances

  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Cytochrome c Group
  • DNA-Binding Proteins
  • NF-kappa B
  • Nitriles
  • Organic Chemicals
  • Peptides
  • Protein Precursors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • SN50 peptide
  • Sesquiterpenes
  • Sesquiterpenes, Guaiane
  • Sulfones
  • parthenolide
  • helenalin
  • DNA
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Caspases
  • Replication Protein C