Glycogen synthase kinase-3β (GSK-3β) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons

Abstract

Glycogen synthase kinase-3β (GSK3β) role in human immunodeficiency virus (HIV)-associated neurodegeneration has been evidenced by previous investigations. In this study, we investigated the specificity of two GSK3β-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 µM, 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 GSK3β inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK3β as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder.

Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors

“…Furthermore, the GSK-3β inhibitors lithium and valproic acid (VPA) can protect against Tat and gp120 mediated neurotoxicity (Dou et al, 2003; Dou et al, 2005; Everall et al, 2002). Rodent and human neurons exposed to culture fluids from HIV-1-infected monocyte-derived macrophages (MDMs) were protected from cell death in the presence GSK-3β inhibitors (lithium, AR-A014418 and 66BIO) (Dou et al, 2005; Nguyen et al, 2009). Importantly, lithium treatment also resulted in neuronal protection and neurogenesis in SCID HIV-1 encephalitis (HIVE) mice (Dou et al, 2005).…”

Role of Neurotrophic Factor Alterations in the Neurodegenerative Process in HIV Associated Neurocognitive Disorders

“…In HIVE, alterations in GSK3β (Maggirwar et al, 1999; Nguyen et al, 2009a, b; Kehn-Hall et al, 2011) and CDK5 (Patrick et al, 2011; Lee et al, 2013) play important roles (Figure 2). Abnormal activation of CDK5 is associated with neurodegenerative disorders, and recently a critical role for CDK5 in adult neurogenesis was identified (Lee et al, 2013).…”

From Tyrian Purple to Kinase Modulators: Naturally Halogenated Indirubins and Synthetic Analogues

“…GSK-3β inhibition with 5IIO has shown a neuroprotective effect and a stress response reduction in human neurons [159]. A similar effect is also observed with HIV-induced neurotoxicity to human neurons where 6BIO was found to significantly reduce the activity of proapoptotic caspases 3,7 [160], and with cortical neuron cells suffering endoplasmic reticulum stress where 6BIO treatment resulted in attenuation of CHOP expression, suggesting a role of this factor in neuronal cell death [161]. In vivo experiments in mice suffering from kainate acid-induced neurotoxicity have shown that brominated indirubin analogues (6BIO, 5BIO, and 5A6BI) reduce mortality and striatal astrogliosis [162].…”