Antioxidants and dipyridamole inhibit HIV-1 gp120-induced free radical-based oxidative damage to human monocytoid cells.
Reactive oxygen species (ROS) may play an important role in HIV-1 pathogenesis and HIV-1 gp120-induced neurotoxicity. Our studies determined the extent to which gp120 increased ROS production in human monocytic U937 cells and the effectiveness of various agents, including dipyridamole (DPR), in blocking these responses. The thiobarbituric acid-reactive substances (TBARS) assay was used as a measure of recombinant gp120 (HIV-1[3B])-induced oxidative damage to U937 cells. As a control, TBARS production was measured using a hypoxanthine/xanthine superoxide generating system. There was gp120-induced oxidative damage in U937 cells with a concentration that produces 50% of maximal effect (apparent EC50 value) of 11 pM. Polyclonal antiserum to gp120 significantly (p < 0.05) inhibited gp120-induced oxidative damage. gp120-induced oxidative damage was significantly inhibited 81% (p < 0.01) by catalase/superoxide dismutase, 53% (p < 0.05) by (+/-)-alpha-tocopherol, 78% (p < 0.01) by desferrioxamine, and 82% (p < 0.01) by ethylene diamine tetraacetic acid (EDTA). These results indicate that gp120 is capable of promoting iron-based oxygen free radical damage to U937 cells. DPR potently (p < 0.05) inhibited both hypoxanthine/xanthine- and gp120-induced oxidative damage with concentrations that produce 50% inhibition (apparent IC50 values) of 1.3 microM for hypoxanthine/xanthine and 1.0 microM for gp120. Therapeutic intervention against ROS production may prevent HIV-1 neurotoxicity.
Foga
I O
IO
Department of Pharmacology, University of Manitoba, Winnipeg, Canada.
Nath
A
A
Hasinoff
B B
BB
Geiger
J D
JD
D019380:Anti-HIV Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015483:HIV Antibodies / Q000097:blood; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000494:pharmacology*; D018023:HIV Seronegativity / Q000276:immunology; D006679:HIV Seropositivity / Q000276:immunology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019820:Xanthine / Q000494:pharmacology
D019380:Anti-HIV Agents; D000975:Antioxidants; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D017382:Reactive Oxygen Species; D019820:Xanthine; D019271:Hypoxanthine; D004176:Dipyridamole