Honkaniemi J, Sharp F R
Department of Neurology, University of California at San Francisco, USA.
J Cereb Blood Flow Metab. 1996 Jul;16(4):557-65. doi: 10.1097/00004647-199607000-00005.
Ischemia induces immediate-early genes (IEGs) in brain. Since prolonged expression of some IEGs may precede neuronal death, some researchers have suggested that these IEGs mediate neuronal death. We therefore examined the effect of 5 and 10 min of global ischemia on the expression of the IEGs NGFI-A, NGFI-B, NGFI-C, egr-2, egr-3, and Nurr1 in gerbil brain. All of the IEGs were induced after 30 min of reperfusion in the hippocampus. Most of them were induced in several other regions as well, including cortex, hypothalamus, thalamus, and amygdala. The acute IEG induction decreased in most brain areas by 2-6 h. However, at 24 h following 5 min of ischemia NGFI-A continued to be expressed in the CA1 region and dentate gyrus. In the dentate gyrus, NGFI-C continued to be expressed for 24 h and egr-3 for as long as 72 h. In other brain areas, all of the IEGs returned to control levels by 72 h except in CA1, where most messenger RNA (mRNA) levels were decreased; this decrease correlated with marked neuronal loss. The persistent expression of NGFI-A in CA1 neurons destined to die and the persistent expression of NGFI-A, NGFI-C, and egr-3 genes in dentate granule cell neurons that survive may indicate that some transcription factors modulate cell death whereas others support cell survival when expressed for prolonged periods. The protein products of several transcription factors, including c-fos, are known to downregulate their own expression. The persistent expression of NGFI-A in the CA1 neurons destined to die could therefore be due to ischemia-induced transcriptional activation caused by, e.g., increased intracellular calcium levels plus a lack of negative feedback caused by the blockade of the translation of NGFI-A mRNA into protein.
脑缺血可诱导脑内即刻早期基因（IEGs）。由于某些即刻早期基因的长时间表达可能先于神经元死亡，一些研究人员认为这些即刻早期基因介导神经元死亡。因此，我们研究了5分钟和10分钟全脑缺血对沙土鼠脑中即刻早期基因NGFI-A、NGFI-B、NGFI-C、egr-2、egr-3和Nurr1表达的影响。海马体再灌注30分钟后，所有即刻早期基因均被诱导表达。其中大多数基因在包括皮质、下丘脑、丘脑和杏仁核在内的其他几个脑区也被诱导表达。多数脑区的急性即刻早期基因诱导在2 - 6小时后下降。然而，缺血5分钟后24小时，NGFI-A在CA1区和齿状回持续表达。在齿状回，NGFI-C持续表达24小时，egr-3持续表达长达72小时。在其他脑区，除CA1区外，所有即刻早期基因在72小时时均恢复到对照水平，CA1区大多数信使核糖核酸（mRNA）水平下降；这种下降与明显的神经元丢失相关。注定死亡的CA1神经元中NGFI-A的持续表达以及存活的齿状颗粒细胞神经元中NGFI-A、NGFI-C和egr-3基因的持续表达可能表明，一些转录因子在长时间表达时调节细胞死亡，而另一些则支持细胞存活。已知包括c-fos在内的几种转录因子的蛋白质产物会下调其自身的表达。因此，注定死亡的CA1神经元中NGFI-A的持续表达可能是由于缺血诱导的转录激活，例如细胞内钙水平升高，加上NGFI-A mRNA翻译成蛋白质的过程受阻导致缺乏负反馈。
