Excitotoxic events underlying ischaemic and traumatic brain injuries activate degenerative and protective pathways, particularly in the hippocampus. To understand opposing pathways that determine the brain's response to excitotoxicity, we used hippocampal explants, thereby eliminating systemic variables during a precise protocol of excitatory stimulation. N-methyl-d-aspartate (NMDA) was applied for 20 min and total RNA isolated one and 24 h later for neurobiology-specific microarrays. Distinct groups of genes exhibited early vs. delayed induction, with 63 genes exclusively reduced 24-h post-insult. Egr-1 and NOR-1 displayed biphasic transcriptional modulation: early induction followed by delayed suppression. Opposing events of NMDA-induced genes linked to pathogenesis and cell survival constituted the early expression signature. Delayed degenerative indicators (up-regulated pathogenic genes, down-regulated pro-survival genes) and opposing compensatory responses (down-regulated pathogenic genes, up-regulated pro-survival genes) generated networks with temporal gene profiles mirroring coexpression network clustering. We then used the expression profiles to test whether NF-κB, a potent transcription factor implicated in both degenerative and protective pathways, is involved in the opposing responses. The NF-κB inhibitor MG-132 indeed altered NMDA-mediated transcriptional changes, revealing components of opposing expression signatures that converge on the single response element. Overall, this study identified counteracting avenues among the distinct responses to excitotoxicity, thereby suggesting multi-target treatment strategies and implications for predictive medicine.

中文翻译：

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兴奋性毒性刺激激活海马中不同的致病性和保护性表达特征

缺血性和创伤性脑损伤背后的兴奋性毒性事件激活退行性和保护性途径，特别是在海马中。为了了解决定大脑对兴奋性毒性反应的相反途径，我们使用了海马外植体，从而在精确的兴奋性刺激方案中消除了系统变量。N-甲基-d- 天冬氨酸 (NMDA) 应用 20 分钟，1 小时和 24 小时后分离总 RNA 用于神经生物学特异性微阵列。不同的基因组表现出早期与延迟诱导，63 个基因在侮辱后 24 小时完全减少。Egr-1 和 NOR-1 显示出双相转录调节：早期诱导后延迟抑制。与发病机制和细胞存活相关的 NMDA 诱导基因的相反事件构成了早期表达特征。延迟的退化指标（上调的致病基因、下调的促生存基因）和相反的补偿反应（下调的致病基因、上调的促生存基因）产生了具有时间基因谱的网络，这些网络反映了共表达网络聚类。然后我们使用表达谱来测试 NF-κB、一种与退化和保护途径有关的有效转录因子，参与相反的反应。NF-κB 抑制剂 MG-132 确实改变了 NMDA 介导的转录变化，揭示了聚集在单一反应元件上的相反表达特征的成分。总体而言，这项研究确定了对兴奋性毒性的不同反应之间的抵消途径，从而提出了多靶点治疗策略和对预测医学的影响。