title: GSK3β-activation is a point of convergence for HIV-1 and opiate-mediated interactive neurotoxicity.
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.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Ruturaj R
authors.initials: RR
authors.lastname: Masvekar
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: peknapp@vcu.edu.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D009020:Morphine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000821:virology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D014635:Valproic Acid; D009020:Morphine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: GSK3β; HIV-1; Morphine; NeuroAIDS; Neurodegeneration; Synaptodendritic injury