Inhibition of tumor necrosis factor-alpha signaling prevents human immunodeficiency virus-1 protein Tat and methamphetamine interaction

Shaji Theodore, Wayne A. Cass, Avindra Nath, Joseph Steiner, Kristie Young, William F. Maragos

Research output: Contribution to journalArticlepeer-review

Abstract

Our previous studies demonstrated that the psychostimulant methamphetamine (MA) and the human immunodeficiency virus-1 (HIV-1) protein Tat interacted to cause enhanced dopaminergic neurotoxicity. The present study examined whether tumor necrosis factor-alpha (TNF-α) mediates the interaction between Tat and MA. In Sprague-Dawley rats, injections of Tat caused a small but significant increase in striatal TNF-α level, whereas MA resulted in no change. The increase in TNF-α induced by Tat + MA was not significantly different from that induced by Tat alone. Temporal analysis of TNF-α levels revealed a 50-fold increase 4 h after Tat administration. In C57BL/6 mice, Tat + MA induced a 50% decline in striatal dopamine levels, which was significantly attenuated in mice lacking both receptors for TNF-α. TNF-α synthesis inhibitors significantly attenuated Tat + MA neurotoxicity in hippocampal neuronal culture. The results suggest that Tat-induced elevation of TNF-α may predispose the dopaminergic terminals to subsequent damage by MA.

Original languageEnglish (US)
Pages (from-to)663-668
Number of pages6
JournalNeurobiology of Disease
Volume23
Issue number3
DOIs
StatePublished - Sep 1 2006

Keywords

  • AIDS
  • Basal ganglia
  • Cytokines
  • Dopamine
  • Drug abuse
  • Neurodegeneration

ASJC Scopus subject areas

  • Neurology

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