Kiessling M, Gass P
Institute of Neuropathology, University of Heidelberg, Germany.
Brain Pathol. 1994 Jan;4(1):77-83. doi: 10.1111/j.1750-3639.1994.tb00813.x.
Glutamate-mediated spreading depression is currently thought to be a key event in the pathogenesis of potential neuronal degeneration in the ischemic 'penumbra'. Glutamate receptor stimulation causes induction of transcription factors that belong to the class of immediate early genes (IEGs), thought to be involved in coupling neuronal excitation to target gene expression. Focal cerebral ischemia elicits a homogeneous expression of several IEGs, prominently in cortex. In the ischemic core, discrepancies are observed between mRNA and protein levels, due to a severe, persistent protein synthesis deficit, preventing the translation of IEG encoded mRNAs. Outside the ischemic core, widespread IEG expression occurs in the entire ipsilateral cortex at mRNA as well as at protein level. This homogeneous expression of transcription factors can be pinpointed to at least two different pathogenetic mechanisms by means of appropriate pharmacological antagonists. Prolonged IEG induction in the 'penumbra', an area in which neurons are metabolically compromised but not yet energy-depleted, cannot be suppressed by the administration of N-methyl-D-aspartate (NMDA) receptor antagonists. In contrast, short-lasting IEG induction in undamaged neurons remote from the ischemic territory, though also caused by ischemia-elicited spreading depression, can be blocked by NMDA receptor antagonists. In both areas, IEG expression identifies neurons destined to survive but is likely to be mediated by different signal transduction pathways, at the receptor, second messenger and/or the DNA level.
目前认为，谷氨酸介导的扩散性抑制是缺血“半暗带”潜在神经元变性发病机制中的关键事件。谷氨酸受体刺激会导致诱导属于即刻早期基因（IEGs）类别的转录因子，这些转录因子被认为参与将神经元兴奋与靶基因表达相偶联。局灶性脑缺血会引发几种IEGs的均匀表达，在皮质中尤为明显。在缺血核心区，由于严重且持续的蛋白质合成缺陷，阻止了IEG编码的mRNA的翻译，因此在mRNA和蛋白质水平之间观察到差异。在缺血核心区之外，整个同侧皮质在mRNA以及蛋白质水平都出现广泛的IEG表达。通过适当的药理学拮抗剂，可以将转录因子的这种均匀表达至少归因于两种不同的发病机制。在“半暗带”（一个神经元代谢受损但尚未能量耗竭的区域）中，长时间的IEG诱导不能被N-甲基-D-天冬氨酸（NMDA）受体拮抗剂所抑制。相比之下，在远离缺血区域的未受损神经元中短暂的IEG诱导，虽然也是由缺血引发的扩散性抑制引起的，但可以被NMDA受体拮抗剂阻断。在这两个区域中，IEG表达都能识别注定存活的神经元，但可能是由受体、第二信使和/或DNA水平上不同的信号转导途径介导的。
