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Cited by 99HIV Research and TreatmentHIV, Drug Use, Sexual RiskHIV/AIDS drug development and treatment

Methamphetamine potentiates HIV-1 Tat protein-mediated activation of redox-sensitive pathways in discrete regions of the brain

Flora, Govinder, Lee, Yong Woo, Nath, Avindra, Hennig, Bernhard, Maragos, William, Toborek, Michal·2003·Experimental Neurology
DOI 10.1006/exnr.2002.8048
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Abstract

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.

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Authors
Flora, G., Lee, Y. W., Nath, A., Hennig, B., Maragos, W., & Toborek, M.
Affiliations
  • University of Kentucky HealthCare (US)
  • University of Kentucky (US)
ORCID
Venue
Experimental Neurology
Publisher
Elsevier BV
Published
2003-01
Volume
179
Issue
1
Pages
60-70
ISSN
0014-4886 (ISSN-L)
DOI
10.1006/exnr.2002.8048
OpenAlex
W2030657267
Cited by
99
References
85
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 7 · 2015: 11 · 2014: 4 · 2013: 3 · 2012: 3
FWCI
1.50
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Experimental Neurology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (MH 63022, R01MH063022)
  • National Institute of Neurological Disorders and Stroke (R01NS039254, NS-39254)
  • National Institute of Environmental Health Sciences (P42ES007380)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Epidemiology › HIV, Drug Use, Sexual Risk
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
HIV-1 Tat protein, methamphetamine, drug abuse, oxidative stress, redox-sensitive transcription factors, NF-κB, AP-1, CREB, ICAM-1, TNF-α, IL-1β, neuroinflammation, hippocampus, striatum, frontal cortex, drug synergy, HIV-associated neurocognitive disorders
MeSH terms
Animals, Brain, Cerebellum, Corpus Striatum, Drug Administration Routes, Drug Synergism, Frontal Lobe, Hippocampus, Interleukin-1, Male, Methamphetamine, Mice, Inbred C57BL, Oxidation-Reduction, Peptide Fragments, Transcription Factors, Tumor Necrosis Factor-alpha, Signal Transduction, HIV-1, Gene Products, tat, Gene Expression, Mutagenesis, Site-Directed, Sequence Deletion, Oxidative Stress, Intercellular Adhesion Molecule-1, Mice, tat Gene Products, Human Immunodeficiency Virus

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