NeuroMolecular Medicine

, Volume 2, Issue 1, pp 71–85 | Cite as

Methamphetamine-induced TNF-α gene expression and activation of AP-1 in discrete regions of mouse brain

Potential role of reactive oxygen intermediates and lipid peroxidation
  • Govinder Flora
  • Yong Woo Lee
  • Avindra Nath
  • William Maragos
  • Bernhard Hennig
  • Michal Toborek
Original Research

Abstract

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-α mRNA were also studied. Expression of the tumor necrosis factor-α (TNF-α) gene was induced 3 h after METH injection and remained elevated for up to 6h of METH exposure. In addition, stimulation of the TNF-α gene was associated with increased TNF-α 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.

Index Entries

Methamphetamine oxidative stress transcription factors AP-1 TNF-α mice brain regions 

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Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Govinder Flora
    • 1
  • Yong Woo Lee
    • 1
  • Avindra Nath
    • 2
    • 3
  • William Maragos
    • 2
    • 4
  • Bernhard Hennig
    • 5
  • Michal Toborek
    • 1
  1. 1.Departments of SurgeryUniversity of KentuckyLexington
  2. 2.Departments of NeurologyUniversity of KentuckyLexington
  3. 3.Departments of Microbiology and ImmunologyUniversity of KentuckyLexington
  4. 4.Departments of Anatomy and NeurobiologyUniversity of KentuckyLexington
  5. 5.Departments of Animal SciencesUniversity of KentuckyLexington

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