p75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures
p75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures
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DOI：
10.1016/s0006-8993(99)02226-x
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发表时间：
2000-01-10
期刊：
影响因子：
2.9
通讯作者：
Shimohama, S
中科院分区：
文献类型：
--
作者：
Kume, T;Nishikawa, H;Shimohama, S
越来越多的证据表明，神经营养素受体Trks和p75在调节细胞生存和死亡方面发挥着不同的作用，其中Trks对细胞生存至关重要，而p75则诱导细胞死亡。在这里，我们提供了证据，在大鼠大脑皮质的神经元培养中，神经生长因子(NGF)通过p75发挥神经保护作用。用NGF孵育培养1-24小时可保护皮层神经元免受短暂谷氨酸所致的迟发性细胞毒性。神经生长因子可减轻钙离子载体、离子霉素或一氧化氮(NO)供体S亚硝基半胱氨酸(SNOC)和3-吗啉四氢呋喃亚胺(SIN-1)所致的迟发性神经毒性。RT-PCR分析显示，在皮质培养物中存在p75和TrkB转录本，但没有检测到NGF的高亲和力受体TrkA的转录本。脑源性神经营养因子(BDNF)，而不是NGF，诱导Trks的酪氨酸磷酸化，表明NGF不激活皮质神经元中的Trks。同时应用抗p75中和抗体可显著降低NGF的神经保护作用，但对BDNF的神经保护作用影响不大。蛋白质合成抑制剂放线菌酮抑制了BDNF诱导的神经保护，而不是NGF诱导的神经保护。不同的信号通路被NGF和BDNF激活，NGF而不是BDNF刺激大量神经酰胺的产生，而BDNF而不是NGF引起丝裂原激活的蛋白激酶的持续激活。这些结果表明，尽管NGF和BDNF都能保护大脑皮层神经元免受兴奋性毒性，但它们的作用机制完全不同。据我们所知，目前的结果首次证明p75主要参与神经营养因子的细胞保护作用。(C)2000 Elsevier Science B.V.保留所有权利。
Accumulating evidence suggests that the neurotrophin receptors, Trks and p75, play distinct roles in regulating cells survival and death, with Trks important for cell survival, and p75 acting to induce cell death. Here, we provide evidence that, in neuronal cultures from rat cerebral cortex, nerve growth factor (NGF) exerts neuroprotective actions via p75. Incubating cultures with NGF for 1-24 h protected cortical neurons from delayed cytotoxicity induced by brief exposure to glutamate. Delayed neurotoxicity induced by a calcium ionophore, ionomycin, or nitric oxide (NO) donors such as S-nitrosocysteine (SNOC) and 3-morpholinosydnonimine (SIN-1), was also attenuated by pretreatment with NGF. RT-PCR analysis revealed the presence of p75 and trkB transcripts in cortical cultures, but did not detect transcripts of trkA, a high-affinity receptor for NGF. Brain-derived neurotrophic factor (BDNF), but not NGF, induced tyrosine phosphorylation of Trks, indicating that NGF does not activate Trks in cortical neurons. Concurrent application of anti-p75 neutralizing antibody markedly reduced the neuroprotective effect of NGF, but resulted in only a modest reduction of that of BDNF. BDNF-induced neuroprotection, but not NGF-induced neuroprotection, was inhibited by a protein synthesis inhibitor cycloheximide. Distinct signaling pathways mobilized by NGF and BDNF were also revealed in that NGF but not BDNF stimulated significant production of ceramides, whereas BDNF but not NGF caused persistent activation of mitogen-activated protein kinases. These results indicate that, although NGF and BDNF both protect cortical neurons from excitotoxicity, the mechanisms involved in their effects are totally different. The present results are, to our knowledge, the first to demonstrate the principal involvement of p75 in cytoprotective actions of neurotrophins. (C) 2000 Elsevier Science B.V. All rights reserved.