Document Detail

Methamphetamine-induced TNF-alpha gene expression and activation of AP-1 in discrete regions of mouse brain: potential role of reactive oxygen intermediates and lipid peroxidation.
MedLine Citation:
PMID:  12230306     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. To study this hypothesis, molecular signaling pathways of METH-induced inflammatory responses via activation of redox-sensitive transcription factors were investigated in discrete regions (corpus striatum, frontal cortex, and hippocampus) of mouse brain. Intraperitoneal injection of METH at a dose of 10 mg/kg body weight resulted in a significant increase in oxidative stress, as measured by 2,7-dichlorofluorescein (DCF) fluorescence assay, thiobarbituric acid-reactive substances (TBARS), and total glutathione levels. Glutathione peroxidase activity was also significantly increased after METH exposure. In addition, DNA binding activity of activator protein-1 (AP-1), a redox-responsive transcription factor, was increased in all studied brain regions in response to METH treatment. Because AP-1 is known to regulate expression of inflammatory genes, levels of TNF-alpha mRNA were also studied. Expression of the tumor necrosis factor-alpha (TNF-alpha) gene was induced 3 h after METH injection and remained elevated for up to 6 h of METH exposure. In addition, stimulation of the TNF-alpha gene was associated with increased TNF-a protein production in the frontal cortex. These results suggest that METH-induced disturbances in cellular redox status and that activation of AP-1 can play a critical role in signaling pathways leading to upregulation of inflammatory genes in vivo. Furthermore, these data provide evidence for the role of oxidative stress in the neurotoxic effects of METH.
Govinder Flora; Yong Woo Lee; Avindra Nath; William Maragos; Bernhard Hennig; Michal Toborek
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neuromolecular medicine     Volume:  2     ISSN:  1535-1084     ISO Abbreviation:  Neuromolecular Med.     Publication Date:  2002  
Date Detail:
Created Date:  2002-09-16     Completed Date:  2003-02-06     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  101135365     Medline TA:  Neuromolecular Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  71-85     Citation Subset:  IM    
Departments of Surgery, University of Kentucky, Lexington 40536, USA.
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MeSH Terms
Brain Chemistry / drug effects*
Central Nervous System Stimulants / administration & dosage,  pharmacology*,  toxicity
Corpus Striatum / drug effects,  metabolism
DNA / genetics,  metabolism
Dopamine Agents / administration & dosage,  pharmacology*,  toxicity
Frontal Lobe / drug effects,  metabolism
Glutathione / analysis
Glutathione Peroxidase / metabolism
Hippocampus / drug effects,  metabolism
Inflammation / genetics
Injections, Intraperitoneal
Lipid Peroxidation / drug effects
Methamphetamine / administration & dosage,  pharmacology*,  toxicity
Mice, Inbred C57BL
Nerve Tissue Proteins / genetics,  metabolism*
Oxidative Stress
Signal Transduction / drug effects
Thiobarbituric Acid Reactive Substances / analysis
Transcription Factor AP-1 / metabolism*
Transcription, Genetic / drug effects
Tumor Necrosis Factor-alpha / biosynthesis*,  genetics
Grant Support
Reg. No./Substance:
0/Central Nervous System Stimulants; 0/Dopamine Agents; 0/Nerve Tissue Proteins; 0/Thiobarbituric Acid Reactive Substances; 0/Transcription Factor AP-1; 0/Tumor Necrosis Factor-alpha; 537-46-2/Methamphetamine; 70-18-8/Glutathione; 9007-49-2/DNA; EC Peroxidase

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