Ridder D A, Schwaninger M
Pharmacological Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Neuroscience. 2009 Feb 6;158(3):995-1006. doi: 10.1016/j.neuroscience.2008.07.007. Epub 2008 Jul 10.
The transcription factor NF-kappaB is a key regulator of hundreds of genes involved in cell survival and inflammation. There is ample evidence that NF-kappaB is activated in cerebral ischemia, mainly in neurons. Despite its well known role as an antiapoptotic factor, in cerebral ischemia NF-kappaB contributes to neuronal cell death, at least if the ischemia is severe enough to lead to irreversible brain damage. In contrast, NF-kappaB also seems to be responsible for the preconditioning effect of a transient and sublethal ischemia, perhaps by dampening its own subsequent full activation. Among the five NF-kappaB subunits, RelA and p50 are responsible for the detrimental effect in cerebral ischemia. Activation of NF-kappaB signaling is mediated by the upstream kinase inhibitor of kappaB kinase and is triggered by hypoxia, reactive oxygen species, and several inflammatory mediators. Interestingly, the complex NF-kappaB signaling pathway provides drug targets at several levels. Modulation of NF-kappaB signaling has the potential to interrupt multiple inflammatory and apoptotic mechanisms through one specific molecular target.
转录因子核因子-κB（NF-κB）是数百个参与细胞存活和炎症的基因的关键调节因子。有充分证据表明，NF-κB在脑缺血中被激活，主要在神经元中。尽管其作为抗凋亡因子的作用众所周知，但在脑缺血中，NF-κB至少在缺血严重到足以导致不可逆脑损伤时会导致神经元细胞死亡。相比之下，NF-κB似乎也负责短暂性和亚致死性缺血的预处理效应，可能是通过抑制其自身随后的完全激活来实现的。在五个NF-κB亚基中，RelA和p50对脑缺血中的有害作用负责。NF-κB信号的激活由κB激酶的上游激酶抑制剂介导，并由缺氧、活性氧和几种炎症介质触发。有趣的是，复杂的NF-κB信号通路在多个水平上提供了药物靶点。调节NF-κB信号有可能通过一个特定的分子靶点中断多种炎症和凋亡机制。
