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• W2079164703 abstract "Neurocognitive deficits are devastating consequences in cancer patients undergoing cranial irradiation due to the damage of hippocampus. We have shown that lithium could effectively be used to protect irradiated hippocampal neurons from apoptosis and improve cognitive performances in irradiated mice. Lithium is known to inhibit GSK-3β, an enzyme that regulates cell fate. Here we demonstrate that small molecule inhibitors of GSK-3β protect hippocampal neurons from radiation-induced apoptosis and increase cell survival. Pharmacodynamic assays were done with the GSK-3β inhibitors to determine the optimal concentration and time of treatment for cultured normal hippocampal neurons (HT-22). Clonogenic survival analysis using GSK-3β inhibitors was performed to evaluate role of GSK-3β in survival of irradiated HT-22 cells. Apoptosis was measured either by morphological assessment of DAPI-stained cells or by flow cytometry of the cells stained with annexin V and propidium iodide. Genetic inhibition of GSK-3β was done by expressing the kinase inactive GSK-3β (KI-GSK-3β) or wild type GSK-3β (WT-GSK-3β) in a bicistronic construct. For analysis of radiation-dependent activation of Akt/GSK-3β pathway, cells were lysed 6 hours after irradiation and subjected to immunoblotting with antibodies to phospho-Akt (Ser473), Akt, β-catenin and Cyclin D1. In animal study, seven-days old C57BL6J pups were treated with SB415286 (1 mg/Kg) and SB216763 (0.6 mg/Kg) followed by irradiation with 7 Gy. Ten hours after irradiation, mice brain tissue was fixed, coronally sectioned and stained with TUNEL. In pharmacodynamic study, we utilized GSK-3β down-stream targets β-catenin to monitor GSK-3β activity. Based on the accumulation of β-catenin in HT-22 cells, the optimal concentrations of GSK-3β inhibitors SB415286, SB216763, AR-AO14418 and BIO were 25 μM, 10 μM, 1 μM and 1 μM respectively. The optimal time of treatment was 16 hours for all four inhibitors. However, when HT-22 cells were treated with GSK-3β inhibitors and 3 Gy of radiation, only pretreatment with SB415286 showed increased accumulation of both β-catenin and cyclin D1. In clonogenic assay, pretreatment of HT-22 with 25 μM SB415286 and 10 μM of SB216763 before irradiation showed statistically significant increase in cell survival as compared to cells treated with radiation alone. Similar effect was observed with genetic inhibition of GSK-3β. To elucidate the mechanism of this increased survival we monitored for program cell death by Annexin V or DAPI staining. In both approaches, inhibition of GSK-3β either genetically with KI-GSK-3β or chemically with SB415286 resulted in a 2-fold decrease in apoptosis as compared to irradiated HT-22 cells. The protective effect of GSK-3β inhibition was also demonstrated in irradiated mice. TUNEL staining of brain sections from treated mice revealed that SB415286 and SB216763 pretreatment protected the hippocampal neurons from radiation-induced apoptosis. Small molecule inhibitors of GSK-3β protect hippocampal neurons from radiation-induced damage in cell culture and animal models. Small molecule inhibitors of GSK-3β could be used as novel therapy for prevention of deleterious neurocognitive consequences of cranial irradiation and improve the quality of life." @default.
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• W2079164703 date "2007-11-01" @default.
• W2079164703 modified "2023-09-27" @default.
• W2079164703 title "Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitors as Radioprotectors of Hippocampal Neurons in the Developing Brain" @default.
• W2079164703 doi "https://doi.org/10.1016/j.ijrobp.2007.07.231" @default.
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