| Publication Abstract Display | | Type: Published Manuscript | | Title: Glycogen synthase kinase-3beta (GSK-3beta) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons. | | Authors: Nguyen TB, Lucero GR, Chana G, Hult BJ, Tatro ET, Masliah E, Grant I, Achim CL, Everall IP, and the HNRC Group | | Year: 2009 | | Publication: Journal of NeuroVirology | | Volume: 15 Issue: 5-6 Pages: 434-438 | | Abstract:Glycogen synthase kinase-3beta (GSK3beta) role in human immunodeficiency virus (HIV)-associated neurodegeneration has been evidenced by previous investigations. In this study, we investigated the specificity of two GSK3beta-specific inhibitors, AR-A014418 (A) and B6B30 (B) to prevent direct neurotoxicity in primary human neurons exposed to HIV (BaL). Neurons were exposed to HIV (500 pg/ml) for 12-h and 6-day periods in the presence and absence of A (1 microM, 100 nM, 10 nM) and B (50 nM, 5 nM, 500 pM) to investigate acute and ongoing mechanisms of HIV neurotoxicity. Using an lactate dehydrogenase (LDH) assay to assess cytotoxicity, we observed a significant neurotoxic effect of HIV from control values (P <.01) that was not restored via coexposures of all concentrations of A and B. Additionally, no change in LDH levels were observed after 6 days. However, activity of the acute proapoptotic markers caspases 3 and 7 using a luminescence assay were measured and found to be increased by exposure to HIV (BaL) compared to controls (P =.022). This effect was ameliorated via coexposure to all concentrations of A and 50 nM B after 12 h (P <.01) and to all concentrations of A and B after 6 days (P <.01). Overall, the results from this study provide further evidence for the ability of GSK3beta inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK3beta as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder. |
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