Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain.
Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain.
复制标题
鉴定通过神经营养素治疗受损大脑中 CA3 神经元上调的潜在神经保护基因。
DOI：
10.1089/neu.2010.1487
复制
发表时间：
2011
影响因子：
4.2
通讯作者：
Watson,DeborahJ
中科院分区：
文献类型：
--
作者：
Malik,SaafanZ;Motamedi,Shahab;Royo,NicolasC;LeBold,David;Watson,DeborahJ
特定的神经营养因子介导创伤性脑损伤（TBI）动物模型的组织学和/或功能改善。在之前的工作中，多项证据表明哺乳动物神经营养蛋白 NT-4/5 对实验性 TBI 后的海马 CA3 锥体神经元具有神经保护作用。我们假设 NT-4/5 神经保护作用是由特定基因组表达的变化介导的，并且 NT-4/5 调节基因是阻止 TBI 后迟发性神经元死亡的潜在治疗靶点。在这项研究中，我们对 CA3 神经元进行了转录谱分析，以确定受侧向液体冲击损伤或 trkB 配体 NT-4/5 或脑源性神经营养因子 (BDNF) 治疗调节的基因。结果表明，神经营养蛋白上调的基因与损伤上调的基因之间存在广泛重叠，这表明神经营养蛋白神经保护背后的机制可能模仿大脑的内源性保护反应。选择用于进一步体外研究的基因子集表现出针对谷氨酸兴奋性毒性的神经保护作用。本研究中确定的神经保护基因在损伤后 30 小时内上调，因此预计在损伤后几小时至几天的临床有用时间范围内发挥作用。通过基因操作或小分子调节这些因素和途径可能会在 TBI 临床前模型中赋予海马神经保护作用。
Specific neurotrophic factors mediate histological and/or functional improvement in animal models of traumatic brain injury (TBI). In previous work, several lines of evidence indicated that the mammalian neurotrophin NT-4/5 is neuroprotective for hippocampal CA3 pyramidal neurons after experimental TBI. We hypothesized that NT-4/5 neuroprotection is mediated by changes in the expression of specific sets of genes, and that NT-4/5-regulated genes are potential therapeutic targets for blocking delayed neuronal death after TBI. In this study, we performed transcription profiling analysis of CA3 neurons to identify genes regulated by lateral fluid percussion injury, or by treatment with the trkB ligands NT-4/5 or brain-derived neurotrophic factor (BDNF). The results indicate extensive overlap between genes upregulated by neurotrophins and genes upregulated by injury, suggesting that the mechanism behind neurotrophin neuroprotection may mimic the brain's endogenous protective response. A subset of genes selected for further studyin vitroexhibited neuroprotection against glutamate excitotoxicity. The neuroprotective genes identified in this study were upregulated at 30 h post-injury, and are thus expected to act during a clinically useful time frame of hours to days after injury. Modulation of these factors and pathways by genetic manipulation or small molecules may confer hippocampal neuroprotectionin vivoin preclinical models of TBI.