Facci Laura, Stevens David A, Skaper Stephen D
Neurophysiology and Cell Sciences, GlaxoSmithKline Research and Development Ltd., Third Avenue, Harlow, Essex CM19 5AW, UK.
Neuroreport. 2003 Aug 6;14(11):1467-70. doi: 10.1097/00001756-200308060-00012.
Protein kinase B (PKB, or Akt), a downstream effector of phosphatidylinositol 3-kinase (PI-3-K), can play a critical role in regulating neuronal survival. Among known targets of PKB, glycogen synthase kinase-3 (GSK-3) is inhibited by PKB-mediated phosphorylation. Recent studies implicate GSK-3 as a physiologically relevant principal regulatory target of the PI-3-K/PKB survival pathway. Here we show that SB-216763 and SB-415286, selective small molecule inhibitors of GSK-3, protected cultured rat cerebellar granule neurons and hippocampal neurons against excitotoxicity mediated by NMDA and non-NMDA receptor agonists. Treatment with SB-216763 and SB-415286 was optimal when initiated 6-7 days before excitotoxin exposure. As GSK-3 can modulate transcriptional events, these results may provide insight into the identification of new neuroprotective targets.
蛋白激酶B（PKB，又称Akt）是磷脂酰肌醇3激酶（PI-3-K）的下游效应物，在调节神经元存活中起关键作用。在已知的PKB作用靶点中，糖原合酶激酶-3（GSK-3）受PKB介导的磷酸化作用抑制。最近的研究表明，GSK-3是PI-3-K/PKB存活途径在生理上相关的主要调节靶点。在此我们表明，GSK-3的选择性小分子抑制剂SB-216763和SB-415286可保护培养的大鼠小脑颗粒神经元和海马神经元免受NMDA和非NMDA受体激动剂介导的兴奋毒性作用。在暴露于兴奋毒素前6 - 7天开始用SB-216763和SB-415286进行处理效果最佳。由于GSK-3可调节转录事件，这些结果可能有助于深入了解新的神经保护靶点的鉴定。
