GSK3beta in ethanol neurotoxicity.
GSK3beta in ethanol neurotoxicity.
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DOI：
10.1007/s12035-009-8075-y
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发表时间：
2009-10
影响因子：
5.1
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Luo J
怀孕期间饮酒是一个重大的公共卫生问题，可能会对孩子造成广泛的不良后果。发育中的中枢神经系统（CNS）对乙醇毒性特别敏感。患有胎儿酒精谱系障碍（FASD）的儿童有各种认知，行为和神经障碍。FASD目前是北美智力迟钝的主要原因，排在唐氏综合症和脑瘫之前。在发育过程中暴露于乙醇会导致大脑中的多种异常，例如神经元的永久性丧失、异位神经元以及突触发生和髓鞘发生的改变。这些酒精诱导的发育中的大脑结构改变是FASD中观察到的许多行为缺陷的基础。然而，乙醇神经毒性的细胞和分子机制仍不清楚。乙醇可缓解细胞应激，包括氧化应激和内质网应激。糖原合成酶激酶3 β（Glycogen synthase kinase 3 β，GSK 3 β）是一种多功能的丝氨酸/苏氨酸激酶，对多种细胞应激有反应。GSK3 β在发育中的CNS中特别丰富，并调节未成熟脑中的多种发育事件，如神经发生和神经元分化、迁移和存活。现有证据表明，乙醇影响CNS中GSK 3 β的活性。GSK3 β抑制提供了对乙醇神经毒性的保护，而高GSK3 β活性/表达使神经元细胞对乙醇诱导的损伤敏感。GSK3 β似乎是一个汇聚信号点，介导了乙醇的一些神经毒性作用。
Alcohol consumption during pregnancy is a significant public health problem and may result in a wide range of adverse outcomes for the child. The developing central nervous system (CNS) is particularly susceptible to ethanol toxicity. Children with fetal alcohol spectrum disorders (FASD) have a variety of cognitive, behavioral, and neurological impairments. FASD currently represents the leading cause of mental retardation in North America ahead of Down syndrome and cerebral palsy. Ethanol exposure during development causes multiple abnormalities in the brain such as permanent loss of neurons, ectopic neurons, and alterations in synaptogenesis and myelinogenesis. These alcohol-induced structural alterations in the developing brain underlie many of the behavioral deficits observed in FASD. The cellular and molecular mechanisms of ethanol neurotoxicity, however, remain unclear. Ethanol elicits cellular stresses, including oxidative stress and endoplasmic reticulum stress. Glycogen synthase kinase 3β (GSK3β), a multifunctional serine/ threonine kinase, responds to various cellular stresses. GSK3β is particularly abundant in the developing CNS, and regulates diverse developmental events in the immature brain, such as neurogenesis and neuronal differentiation, migration, and survival. Available evidence indicates that the activity of GSK3β in the CNS is affected by ethanol. GSK3β inhibition provides protection against ethanol neurotoxicity, whereas high GSK3β activity/expression sensitizes neuronal cells to ethanol-induced damages. It appears that GSK3β is a converging signaling point that mediates some of ethanol’s neurotoxic effects.