Methamphetamine potentiates HIV-1 Tat protein-mediated activation of redox-sensitive pathways in discrete regions of the brain.
Tat is a major regulatory protein encoded by human immunodeficiency viral genome, which has been implicated in the pathogenesis of HIV infection, including neurologic complications associated with this disease. In addition, drug abuse has been identified as a major risk factor of HIV infection. We hypothesize that abusive drugs, such as methamphetamine (METH), can directly influence specific molecular processes that can further contribute to toxic effects of Tat. To elucidate the molecular signaling pathways of Tat- and/or METH-induced toxicity, we investigated the effects of a single injection of Tat (25 microg/microl into the right hippocampus) and/or METH (10 mg/kg, intraperitoneally) on the generation of cellular oxidative stress, DNA-binding activity of specific redox-responsive transcription factors, and expression of inflammatory genes. Administration of Tat or METH resulted in stimulation of cellular oxidative stress and activation of redox-regulated transcription factors in the cortical, striatal, and hippocampal regions of the mouse brain. In addition, DNA-binding activities of NF-kappaB, AP-1, and CREB in the frontal cortex and hippocampus were more pronounced in mice injected with Tat plus METH compared to the effects of Tat or METH alone. Intercellular adhesion molecule-1 gene expression also was upregulated in a synergistic manner in cortical, striatal, and hippocampal regions in mice which received injections of Tat combined with METH compared to the effects of these agents alone. Moreover, synergistic effects of Tat plus METH on the tumor necrosis factor-alpha and interleukin-1beta mRNA levels were observed in the striatal region. These results indicate that Tat and METH can cross-amplify their cellular effects, leading to alterations of redox-regulated inflammatory pathways in the brain. Such synergistic proinflammatory stimulation may have significant implications in HIV-infected patients who abuse drugs.
Flora
Govinder
G
Department of Surgery, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536, USA.
Lee
Yong Woo
YW
Nath
Avindra
A
Hennig
Bernhard
B
Maragos
William
W
Toborek
Michal
M
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004333:Drug Administration Routes; D004357:Drug Synergism; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D015696:Gene Products, tat / Q000235:genetics / Q000494:pharmacology*; D015497:HIV-1; D006624:Hippocampus / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D007375:Interleukin-1; D010446:Peptide Fragments; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D018799:Intercellular Adhesion Molecule-1; D008694:Methamphetamine