title: Neuroadaptations in human chronic alcoholics: dysregulation of the NF-kappaB system.
abstract: BACKGROUND
  Alcohol dependence and associated cognitive impairments apparently result from neuroadaptations to chronic alcohol consumption involving changes in expression of multiple genes. Here we investigated whether transcription factors of Nuclear Factor-kappaB (NF-kappaB) family, controlling neuronal plasticity and neurodegeneration, are involved in these adaptations in human chronic alcoholics.
  
  
  RESULTS
  Analysis of DNA-binding of NF-kappaB (p65/p50 heterodimer) and the p50 homodimer as well as NF-kappaB proteins and mRNAs was performed in postmortem human brain samples from 15 chronic alcoholics and 15 control subjects. The prefrontal cortex involved in alcohol dependence and cognition was analyzed and the motor cortex was studied for comparison. The p50 homodimer was identified as dominant kappaB binding factor in analyzed tissues. NF-kappaB and p50 homodimer DNA-binding was downregulated, levels of p65 (RELA) mRNA were attenuated, and the stoichiometry of p65/p50 proteins and respective mRNAs was altered in the prefrontal cortex of alcoholics. Comparison of a number of p50 homodimer/NF-kappaB target DNA sites, kappaB elements in 479 genes, down- or upregulated in alcoholics demonstrated that genes with kappaB elements were generally upregulated in alcoholics. No significant differences between alcoholics and controls were observed in the motor cortex.
  
  
  CONCLUSIONS
  We suggest that cycles of alcohol intoxication/withdrawal, which may initially activate NF-kappaB, when repeated over years downregulate RELA expression and NF-kappaB and p50 homodimer DNA-binding. Downregulation of the dominant p50 homodimer, a potent inhibitor of gene transcription apparently resulted in derepression of kappaB regulated genes. Alterations in expression of p50 homodimer/NF-kappaB regulated genes may contribute to neuroplastic adaptation underlying alcoholism.
authors: The Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors: Anna
authors: A
authors: Okvist
authors: Sofia
authors: S
authors: Johansson
authors: Alexander
authors: A
authors: Kuzmin
authors: Igor
authors: I
authors: Bazov
authors: Roxana
authors: R
authors: Merino-Martinez
authors: Igor
authors: I
authors: Ponomarev
authors: R Dayne
authors: RD
authors: Mayfield
authors: R Adron
authors: RA
authors: Harris
authors: Donna
authors: D
authors: Sheedy
authors: Therese
authors: T
authors: Garrick
authors: Clive
authors: C
authors: Harper
authors: Yasmin L
authors: YL
authors: Hurd
authors: Lars
authors: L
authors: Terenius
authors: Tomas J
authors: TJ
authors: Ekström
authors: Georgy
authors: G
authors: Bakalkin
authors: Tatjana
authors: T
authors: Yakovleva
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002908:Chronic Disease; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D004247:DNA; D051550:I-kappa B Kinase