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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

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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.

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Authors and Affiliations

  1. Departments of Surgery, University of Kentucky, 40536, Lexington, KY

    Govinder Flora, Yong Woo Lee & Michal Toborek

  2. Departments of Neurology, University of Kentucky, 40536, Lexington, KY

    Avindra Nath & William Maragos

  3. Departments of Microbiology and Immunology, University of Kentucky, 40536, Lexington, KY

    Avindra Nath

  4. Departments of Anatomy and Neurobiology, University of Kentucky, 40536, Lexington, KY

    William Maragos

  5. Departments of Animal Sciences, University of Kentucky, 40536, Lexington, KY

    Bernhard Hennig

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  1. Govinder Flora
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  2. Yong Woo Lee
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Flora, G., Lee, Y.W., Nath, A. et al. Methamphetamine-induced TNF-α gene expression and activation of AP-1 in discrete regions of mouse brain. Neuromol Med 2, 71–85 (2002). https://doi.org/10.1385/NMM:2:1:71

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