Neurology Medical News about AR-A014418, B6B30, caspase, GSK-3β, HIV, neurotoxicity

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Glycogen synthase kinase-3β (GSK-3β) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons
Journal of Neurovirology, 08/21/09

Nguyen TB et al. – Results support the ability of glycogen synthase kinase-3β (GSK-3β) inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK-3β as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder.

Methods

Study of the specificity of 2 GSK-3β-specific inhibitors, AR-A014418 (A) and B6B30 (B) to prevent direct neurotoxicity in primary human neurons exposed to HIV (BaL)
Investigation of acute and ongoing mechanisms of HIV neurotoxicity
Exposure of neurons to HIV (500 pg/mL) for 12-hr and 6-day periods in presence/absence of A (1 µM, 100 nM, 10 nM) and B (50 nM, 5 nM, 500 pM)
Lactate dehydrogenase (LDH) assay to assess cytotoxicity
Luminescence assay to measure activity of acute proapoptotic markers caspases 3 and 7

Results

Significant neurotoxic effect of HIV from control values was not restored via coexposures of all concentrations of A and B
No change in LDH levels after 6 days
Acute proapoptotic markers caspases 3 and 7 activity increased by HIV exposure (BaL) vs controls
Effect ameliorated via coexposure to all concentrations of A and 50 nM B after 12 hr and to all concentrations of A and B after 6 days

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