Lack of the p50 Subunit of Nuclear Factor-κB Increases the Vulnerability of Hippocampal Neurons to Excitotoxic Injury
Lack of the p50 Subunit of Nuclear Factor-κB Increases the Vulnerability of Hippocampal Neurons to Excitotoxic Injury
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DOI：
10.1523/jneurosci.19-20-08856.1999
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发表时间：
1999-10
期刊：
影响因子：
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通讯作者：
Zaifang Yu;Daohong Zhou;A. Bruce-Keller;M. Kindy;M. Mattson
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文献类型：
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作者：
Zaifang Yu;Daohong Zhou;A. Bruce-Keller;M. Kindy;M. Mattson
核因子-κB(核因子-κB)在包括脑缺血和癫痫发作在内的各种损伤后在脑细胞中被激活。尽管细胞培养研究表明，激活NF-κB可以防止神经细胞凋亡，但该转录因子在体内神经元损伤中的作用尚不清楚，涉及的特异性κB亚单位也不清楚。我们现在报告，缺乏p50亚单位的NF-κB的小鼠在给予激毒素海人藻酸盐后，表现出对海马锥体神经元的损伤增加。凝胶位移分析表明，p50是海马区大部分κBDNA结合活性所必需的。野生型小鼠脑室注射κB诱骗DNA后，海人藻酸盐对海马神经元的损伤作用增强，提示NF-κB活性降低足以解释p50−/−小鼠兴奋性毒性神经元损伤加重的原因。与p50+/+和p50+/−小鼠相比，p50+/+和p50+/−小鼠培养的海马神经元在谷氨酸暴露后表现出细胞内钙水平的升高和氧化应激水平的增加，并且更容易受到兴奋毒性的影响。总而言之，我们的数据显示了NF-κB的p50亚单位在保护神经元免受兴奋性毒性细胞死亡中的重要作用。
Nuclear factor-κB (NF-κB) is activated in brain cells after various insults, including cerebral ischemia and epileptic seizures. Although cell culture studies have suggested that the activation of NF-κB can prevent neuronal apoptosis, the role of this transcription factor in neuronal injury in vivo is unclear, and the specific κB subunits involved are unknown. We now report that mice lacking the p50 subunit of NF-κB exhibit increased damage to hippocampal pyramidal neurons after administration of the excitotoxin kainate. Gel-shift analyses showed that p50 is required for the majority of κB DNA-binding activity in hippocampus. Intraventricular administration of κB decoy DNA before kainate administration in wild-type mice resulted in an enhancement of damage to hippocampal pyramidal neurons, indicating that reduced NF-κB activity was sufficient to account for the enhanced excitotoxic neuronal injury in p50−/− mice. Cultured hippocampal neurons from p50−/− mice exhibited enhanced elevations of intracellular calcium levels and increased levels of oxidative stress after exposure to glutamate and were more vulnerable to excitotoxicity than were neurons from p50+/+ and p50+/− mice. Collectively, our data demonstrate an important role for the p50 subunit of NF-κB in protecting neurons against excitotoxic cell death.