Document Detail

Methamphetamine induces AP-1 and NF-kappaB binding and transactivation in human brain endothelial cells.
MedLine Citation:
PMID:  11746378     Owner:  NLM     Status:  MEDLINE    
Cellular and molecular mechanisms of methamphetamine (METH)-induced neurotoxicity may involve alterations of cellular redox status and induction of inflammatory genes in endothelial cells. To study these hypotheses, molecular signaling pathways of METH-induced inflammatory responses via activation of redox-sensitive transcription factors were investigated in human brain microvascular endothelial cells (HBMEC). A dose-dependent depletion of total glutathione levels was detected in HBMEC exposed to METH. In addition, electrophoretic mobility shift assay (EMSA) showed significant increases in DNA binding activities of redox-responsive transcription factors, AP-1 and NF-kappaB, in HBMEC treated with METH. METH-mediated AP-1 or NF-kappaB activation was accompanied by induction of transactivation of AP-1 or NF-kappaB, as measured by dual luciferase assay using specific reporter plasmids. Because NF-kappaB and AP-1 are known to regulate expression of inflammatory genes, expression of the gene encoding for tumor necrosis factor-alpha (TNF-alpha) was also studied in METH-treated HBMEC. A dose-dependent overexpression of the TNF-alpha gene was observed in HBMEC treated with METH. The importance of AP-1 and NF-kappaB in METH-induced TNF-alpha gene was confirmed in functional promoter studies using constructs of the TNF-alpha promoter with mutated AP-1 or NF-kappaB sites. These results indicate that METH-induced disturbances in cellular redox status and activation of AP-1 and NF-kappaB can play critical roles in the signaling pathways leading to upregulation of inflammatory genes in human brain endothelial cells.
Y W Lee; B Hennig; J Yao; M Toborek
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neuroscience research     Volume:  66     ISSN:  0360-4012     ISO Abbreviation:  J. Neurosci. Res.     Publication Date:  2001 Nov 
Date Detail:
Created Date:  2001-12-17     Completed Date:  2002-01-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7600111     Medline TA:  J Neurosci Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  583-91     Citation Subset:  IM    
Copyright Information:
Copyright 2001 Wiley-Liss, Inc.
Department of Surgery, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
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MeSH Terms
Amphetamine-Related Disorders / genetics,  metabolism,  physiopathology
Binding Sites / drug effects,  physiology
Blood-Brain Barrier / drug effects,  physiology
Brain / drug effects*,  metabolism,  physiopathology
Cells, Cultured / drug effects,  metabolism
Encephalitis / chemically induced,  genetics*,  metabolism
Endothelium, Vascular / drug effects*,  metabolism,  physiopathology
Gene Expression Regulation / drug effects,  physiology
Genes, Reporter / drug effects,  physiology
Glutathione / drug effects,  metabolism
Methamphetamine / toxicity*
Microcirculation / drug effects,  metabolism,  physiopathology
NF-kappa B / drug effects*,  genetics,  metabolism
Oxidation-Reduction / drug effects
Oxidative Stress / drug effects*,  genetics
RNA, Messenger / drug effects,  metabolism
Signal Transduction / drug effects,  genetics
Transcription Factor AP-1 / drug effects*,  genetics,  metabolism
Transcription, Genetic / drug effects,  physiology
Tumor Necrosis Factor-alpha / drug effects,  genetics,  metabolism
Grant Support
Reg. No./Substance:
0/NF-kappa B; 0/RNA, Messenger; 0/Transcription Factor AP-1; 0/Tumor Necrosis Factor-alpha; 537-46-2/Methamphetamine; 70-18-8/Glutathione

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