TY - JOUR
T1 - Methamphetamine potentiates HIV-1 Tat protein-mediated activation of redox-sensitive pathways in discrete regions of the brain
AU - Flora, Govinder
AU - Lee, Yong Woo
AU - Nath, Avindra
AU - Hennig, Bernhard
AU - Maragos, William
AU - Toborek, Michal
PY - 2003
Y1 - 2003
N2 - 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 μg/μl 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-κB, 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-α and interleukin-1β 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.
AB - 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 μg/μl 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-κB, 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-α and interleukin-1β 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.
KW - Adhesion molecule
KW - Brain regions
KW - Cytokines
KW - HIV-1
KW - Methamphetamine
KW - Oxidative stress
KW - Tat
KW - Transcription factors
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U2 - 10.1006/exnr.2002.8048
DO - 10.1006/exnr.2002.8048
M3 - Article
C2 - 12504868
AN - SCOPUS:0037229559
VL - 179
SP - 60
EP - 70
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
IS - 1
ER -