Pennypacker K R, Kassed C A, Eidizadeh S, O'Callaghan J P
University of South Florida, College of Medicine, Department of Pharmacology and Therapeutics, 12901 Bruce B. Downs Boulevard MDC 9, Tampa, FL 33612, USA.
Acta Neurobiol Exp (Wars). 2000;60(4):515-30. doi: 10.55782/ane-2000-1373.
A specific temporal order of events at the cellular and molecular level occurs in response to injury to the brain. Injury-compromised neurons degenerate while surviving neurons undergo neuritogenesis and synaptogenesis to establish neuronal connectivity destroyed in the injury. Several genes, such as those coding cytoskeletal proteins and growth factors, have been shown to be regulated by AP-1 and NF-kappa B transcription factors, two of the most studied DNA binding regulatory proteins. Our laboratory has discovered that Fos-related antigen-2 from AP-1 transcription factor family and NF-kappa B p65 and p50 subunits are induced long-term (days to months) in the brain after neurotoxic, excitotoxic or ischemic insult. Fos-related antigen-2 is induced in neurons in several models of injury and its elevated expression lasts days to months, corresponding to the severity. The time-course of FRA-2 induction is abbreviated with less severe insult (terminal damage) relative to the cell death, but the induction occurs during the period of regeneration and repair in both models. NF-kappa B p65 is basally expressed in hippocampal and cortical neurons, but is elevated in reactive astrocytes in hippocampus and entorhinal cortex starting at two days and lasting at least two weeks after kainate treatment. Neurons of the hippocampus surviving ischemic or neurotoxic injury increase expression of NF-kappa B p50 for at least a week after injury, suggesting a function for p50 in neuronal survival and/or repair. The extended expression of these transcription factors implies a role in the activation of genes related to repair and regeneration, such as growth factors and synaptic proteins, after injury to the CNS.
针对脑损伤，细胞和分子水平会出现特定的事件时间顺序。受损的神经元会退化，而存活的神经元则会经历神经突发生和突触发生，以建立损伤中被破坏的神经元连接。一些基因，如编码细胞骨架蛋白和生长因子的基因，已被证明受AP-1和NF-κB转录因子调控，这是两种研究最多的DNA结合调节蛋白。我们实验室发现，AP-1转录因子家族中的Fos相关抗原2以及NF-κB p65和p50亚基在神经毒性、兴奋性毒性或缺血性损伤后会在脑中被长期（数天至数月）诱导。在几种损伤模型中，Fos相关抗原2在神经元中被诱导，其表达升高持续数天至数月，与损伤的严重程度相对应。相对于细胞死亡，较轻的损伤（终末损伤）会使FRA-2诱导的时间进程缩短，但在两种模型的再生和修复期都会发生诱导。NF-κB p65在海马和皮质神经元中基础表达，但在海藻酸处理后两天开始，在海马和内嗅皮质的反应性星形胶质细胞中升高，并持续至少两周。海马中在缺血或神经毒性损伤后存活的神经元在损伤后至少一周内NF-κB p50的表达增加，提示p50在神经元存活和/或修复中发挥作用。这些转录因子的延长表达意味着在中枢神经系统损伤后，它们在激活与修复和再生相关的基因（如生长因子和突触蛋白）方面发挥作用。
