Glycogen synthase kinase-3beta (GSK-3beta) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons.
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.
Nguyen
Timothy B
TB
Department of Psychiatry, HIV Neurobehavioral Research Center, University of California, San Diego, California 92093-0603, USA.
Lucero
Ginger R
GR
Chana
Gursharan
G
Hult
Britta J
BJ
Tatro
Erick T
ET
Masliah
Eliezer
E
Grant
Igor
I
Achim
Cristian L
CL
Everall
Ian P
IP
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000473:pathology / Q000821:virology; D009336:Necrosis; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000821:virology; D010091:Oximes / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C483321:6-bromoindirubin-3'-oxime; D004791:Enzyme Inhibitors; D007211:Indoles; D010091:Oximes; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D007770:L-Lactate Dehydrogenase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
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