Differential effects of BDNF, ADNF9, and TNFα on levels of NMDA receptor subunits, calcium homeostasis, and neuronal vulnerability to excitotoxicity
Differential effects of BDNF, ADNF9, and TNFα on levels of NMDA receptor subunits, calcium homeostasis, and neuronal vulnerability to excitotoxicity
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DOI：
10.1006/exnr.1999.7242
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发表时间：
2000-02-01
影响因子：
5.3
通讯作者：
Mattson, MP
中科院分区：
文献类型：
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作者：
Glazner, GW;Mattson, MP
通过N-甲基-D-天冬氨酸（NMDA）受体的钙内流可导致神经元凋亡或坏死，并可能在许多不同的神经退行性疾病中的神经元死亡中起关键作用。在本研究中，我们采用原代神经元培养和三种不同的兴奋性保护因子，脑源性神经营养因子（BDNF），活动依赖性神经营养因子（ADNF 9），和肿瘤坏死因子α（TNF α），阐明营养因子修改兴奋性毒性过程的机制。用BDNF预处理的神经元表现出NMDA受体亚单位NR 1和NR 2A水平的增加，这与NMDA的钙反应增加和易受兴奋性毒性坏死的影响以及易受凋亡的影响减少有关。ADNF 9和TNF α抑制钙对谷氨酸的反应，并保护神经元免受兴奋性毒性坏死和凋亡，但对NMDA受体亚单位的水平没有影响。H7和KB诱饵DNA分别抑制NF-κ B的磷酸化和DNA结合，表明BDNF的清除毒性调节作用是由激酶介导的，而ADNF 9和TNF α的清除毒性调节作用是由激酶和转录因子NF-κ B介导的。我们的数据表明，BDNF增加神经元对谷氨酸的反应，而ADNF 9和TNF α降低相同，所有三个保护兴奋性毒性细胞凋亡。(C)北京大学出版社.
Calcium influx through N-methyl-D-aspartate (NMDA) receptors can result in neuronal apoptosis or necrosis and may play a pivotal role in neuronal death in many different neurodegenerative diseases. In the present study we employed primary neuronal cultures and three different excitoprotective factors, brain-derived neurotrophic factor (BDNF), activity-dependent neurotrophic factor (ADNF9), and tumor necrosis factor alpha (TNF alpha), to elucidate the mechanisms whereby trophic factors modify the excitotoxic process. Neurons pretreated with BDNF exhibited increased levels of the NMDAreceptor subunits NR1 and NR2A which was associated with increased calcium responses to NMDA and vulnerability to excitotoxic necrosis and reduced vulnerability to apoptosis. ADNF9 and TNF alpha suppressed calcium responses to glutamate and protected neurons against both excitotoxic necrosis and apoptosis, but had no effect on levels of NMDA receptor subunits. Inhibition of phosphorylation and DNA binding of NF-kappa B, by H7 and KB decoy DNA, respectively; suggest that the extitotoxic-modulating actions of BDNF are mediated by kinases, while those of ADNF9 and TMF alpha are mediated by both kinases and the transcription factor NF-kappa B. Our data show that, whereas BDNF increases neuronal responses to glutamate while ADNF9 and TNF alpha decrease the same, all three protect against excitotoxic apoptosis. (C) 2000 Academic Press.