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Publication Abstract Display
Type: Published Abstract
Title: GSK-3 specific inhibitors provide neuroprotection against gp-120-mediated toxicity.
Authors: Lucero GR, Chana G, Hult BJ, Tatro ET, Achim CL, Masliah E, Grant I, Everall IP
Year: 2008
Publication: Society for Biological Psychiatry Annual Meeting, Washington, DC
Volume: Issue: Pages: 274
Abstract:Background We have previously demonstrated that the HIV envelope glycoprotein (gp120) is capable of causing direct toxicity in primary neuronal cultures. This mechanism of toxicity is thought to be mediated through the GSK3β pathway and contribute to the neuronal loss observed in the brains of patients with HIV. In this study, the neuroprotective effects of GSK-3β specific inhibitors were evaluated by their ability to prevent HIV-gp120-mediated neurotoxicity. Methods Primary human fetal neuronal cultures were exposed to gp120 (BAL) at 100ng/ml for a period up to six days in the presence and absence of GSK-3β specific inhibitors AR-A014418 and B6B30 at established non-toxic concentrations. Toxicity was measured using a standard lactate dehydrogenase assay. The inhibitors were also assayed for their ability to decrease the activity of apoptotic effector proteins, caspase-3 and caspase-7, in the presence of gp120 or viral supernatants. Results The LDH and caspase assays both demonstrated the beneficial effects of inhibiting GSK3β on cell survival. At day six, LDH levels of gp120 treated samples were significantly elevated compared to untreated samples (p<0.001). However, LDH levels of samples co-incubated with gp120 and GSK-3β inhibitors were similar to those of controls (p>0.10). Similarly, levels of active caspase were decreased when inhibitors were co-incubated with gp120 or viral supernatants compared to virus and gp120 alone. Conclusions We have demonstrated that the GSK-3β inhibitors AR-A014418 and B6B30 provide protection against gp120-mediated neurotoxicity. Our future work will focus on further cellular characterization of GSK-3β mediated neuroprotection as well as assessing associated downstream transcriptional events.

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