Inhibition of tumor necrosis factor-alpha signaling prevents human immunodeficiency virus-1 protein Tat and methamphetamine interaction.
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-alpha) mediates the interaction between Tat and MA. In Sprague-Dawley rats, injections of Tat caused a small but significant increase in striatal TNF-alpha level, whereas MA resulted in no change. The increase in TNF-alpha induced by Tat + MA was not significantly different from that induced by Tat alone. Temporal analysis of TNF-alpha 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-alpha. TNF-alpha synthesis inhibitors significantly attenuated Tat + MA neurotoxicity in hippocampal neuronal culture. The results suggest that Tat-induced elevation of TNF-alpha may predispose the dopaminergic terminals to subsequent damage by MA.
Theodore
Shaji
S
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Cass
Wayne A
WA
Nath
Avindra
A
Steiner
Joseph
J
Young
Kristie
K
Maragos
William F
WF
D015526:AIDS Dementia Complex / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D019969:Amphetamine-Related Disorders / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D004660:Encephalitis / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D015696:Gene Products, tat / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000276:immunology / Q000821:virology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus
D018765:Dopamine Uptake Inhibitors; D015696:Gene Products, tat; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine; D004298:Dopamine