Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol-3-kinase
Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol-3-kinase
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DOI：
10.1097/00000374-200005000-00017
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发表时间：
2000-05-01
影响因子：
3.2
通讯作者：
Wands, JR
中科院分区：
文献类型：
--
作者：
de la Monte, SM;Ganju, N;Wands, JR
背景资料：乙醇对胰岛素信号通路的抑制可能导致胎儿酒精综合征和与酒精性神经变性相关的脑萎缩中中枢神经系统（CNS）发育受损。先前的研究表明，乙醇抑制胰岛素刺激的PNET 2 CNS衍生的增殖（未成熟）神经元细胞的生长。我们现在提供的证据表明，乙醇在胰岛素刺激的PNET 2细胞中的生长抑制作用部分是由于凋亡。方法：对照和乙醇处理的PNET 2细胞用胰岛素刺激，并分析活力，凋亡，促凋亡和存活基因表达和信号通路的激活，以及半胱天冬酶激活的证据。乙醇处理的PNET 2神经元细胞表现出p53和磷酸氨基末端c-jun激酶水平升高介导的凋亡增加（磷酸-JNK），以及Bcl-2、磷酸肌醇3-激酶（PI 3 K）和完整（类似于116 kD）聚（ADP核糖）聚合酶（PARP）（脱氧核糖核酸修复酶和胱天蛋白酶3的重要底物）的水平降低。通过在含有2%胎牛血清而不是胰岛素或胰岛素加I型胰岛素样生长因子或神经生长因子的培养基中培养细胞，实现乙醇诱导的神经元细胞死亡的部分拯救。由此产生的增强活力与p53和磷酸化JNK水平降低和PI 3 K和完整PARP水平增加有关。结论：研究结果表明，乙醇诱导的胰岛素刺激的神经元细胞凋亡可以通过激活PI 3 K和抑制促凋亡基因表达和细胞内信号通过非胰岛素依赖性途径减少。
Background: Ethanol inhibition of insulin signaling pathways may contribute to impaired central nervous system (CNS) development in the fetal alcohol syndrome and brain atrophy associated with alcoholic neurodegeneration. Previous studies demonstrated ethanol inhibition of insulin-stimulated growth in PNET2 CNS-derived proliferative (immature) neuronal cells. We now provide evidence that the growth-inhibitory effect of ethanol in insulin-stimulated PNET2 cells is partly due to apoptosis.Methods: Control and ethanol-treated PNET2 cells were stimulated with insulin and analyzed for viability, apoptosis, activation of pro-apoptosis and survival gene expression and signaling pathways, and evidence of caspase activation.Results: Ethanol-treated PNET2 neuronal cells exhibited increased apoptosis mediated by increased levels of p53 and phospho-amino-terminal c-jun kinase (phospho-JNK), and reduced levels of Bcl-2, phosphoinositol 3-kinase (PI3 K), and intact (similar to 116 kD) poly (ADP ribose) polymerase (PARP), a deoxyribonucleic acid repair enzyme and important substrate for caspase 3. Partial rescue from ethanol-induced neuronal cell death was effected by culturing the cells in medium that contained 2% fetal calf serum instead of insulin, or insulin plus either insulin-like growth factor type I or nerve growth factor. The resulting enhanced viability was associated with reduced levels of p53 and phospho-JNK and increased levels of PI3 K and intact PARP.Conclusions: The findings suggest that ethanol-induced apoptosis of insulin-stimulated neuronal cells can be reduced by activating PI3 K and inhibiting pro-apoptosis gene expression and intracellular signaling through non-insulin-dependent pathways.