Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8478569 | Molecular and Cellular Neuroscience | 2015 | 10 Pages |
Abstract
Infection of the CNS with HIV-1 occurs rapidly after primary peripheral infection. HIV-1 can induce a wide range of neurological deficits, collectively known as HIV-1-associated neurocognitive disorders. Our previous work has shown that the selected neurotoxic effects induced by individual viral proteins, Tat and gp120, and by HIV+ supernatant are enhanced by co-exposure to morphine. This mimics co-morbid neurological effects observed in opiate-abusing HIV+ patients. Although there is a correlation between opiate drug abuse and progression of HIV-1-associated neurocognitive disorders, the mechanisms underlying interactions between HIV-1 and opiates remain obscure. Previous studies have shown that HIV-1 induces neurotoxic effects through abnormal activation of GSK3β. Interestingly, expression of GSK3β has shown to be elevated in brains of young opiate abusers indicating that GSK3β is also linked to neuropathology seen with opiate-abusing patients. Thus, we hypothesize that GSK3β activation is a point of convergence for HIV- and opiate-mediated interactive neurotoxic effects. Neuronal cultures were treated with supernatant from HIV-1SF162-infected THP-1 cells, in the presence or absence of morphine and GSK3β inhibitors. Our results show that GSK3β inhibitors, including valproate and small molecule inhibitors, significantly reduce HIV-1-mediated neurotoxic outcomes, and also negate interactions with morphine that result in cell death, suggesting that GSK3β-activation is an important point of convergence and a potential therapeutic target for HIV- and opiate-mediated neurocognitive deficits.
Keywords
NF-κBdouble-stranded RNA-activated protein kinaseTrans-activator of transcriptionHSF-1FGFsNeuroAIDSVPAPKRGSK3βCARTMAP-2cdk5gp120PSD-95CREBPI3KGAPDHHDACAP-1TATNeurodegenerationcombination antiretroviral therapyHandCNSValproatecentral nervous systemcyclin-dependent kinase 5Fibroblast Growth FactorsHeat shock factor-1Nuclear factor-kappa Bphosphatidylinositol-3-kinaseMORsmorphinehistone deacetylaseHIV-1human immunodeficiency virus-1cyclic AMP response element binding proteinactivator protein 1microtubule-associated protein 2postsynaptic density protein 95glyceraldehyde 3-phosphate dehydrogenaseGlycogen synthase kinase-3βGlycoprotein 120μ-opioid receptors
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Authors
Ruturaj R. Masvekar, Nazira El-Hage, Kurt F. Hauser, Pamela E. Knapp,