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2579438 
Journal Article 
Glycogen synthase kinase-3 beta (GSK-3 beta) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons 
Nguyen, TB; Lucero, GR; Chana, G; Hult, BJ; Tatro, ET; Masliah, E; Grant, I; Achim, CL; Everall, I; HIV Neurobehav Res Grp 
2009 
Yes 
Journal of NeuroVirology
ISSN: 1355-0284 
15 
5-6 
434-438 
English 
19688630 
WOS:000276076900009 
Glycogen synthase kinase-3 beta (GSK3 beta) role in human immunodeficiency virus (HIV)-associated neurodegeneration has been evidenced by previous investigations. In this study, we investigated the specificity of two GSK3 beta-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 mu M, 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 GSK3 beta inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK3 beta as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder. Journal of Neuro Virology (2009) 15, 434-438. 
AR-A014418; B6B30; caspase; GSK3 beta; HIV; neurotoxicity