Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Stroke. 2010 Oct;41(10 Suppl):S64-71. doi: 10.1161/STROKEAHA.110.595298.
Notch receptors (1-4) are membrane proteins that, on ligand stilumation, release their cytoplasmic domains to serve as transcription factors. Notch-2 promotes proliferation both during development and cancer, but its role in response to ischemic injury is less well understood. The purpose of this study was to understand whether Notch-2 is induced after neonatal stroke and to investigate its functional relevance.
P12 CD1 mice were subjected to permanent unilateral (right-sided) double ligation of the common carotid artery.
Neonatal ischemia induces a progressive brain injury with prolonged apoptosis and Notch-2 up-regulation. Notch-2 expression was induced shortly after injury in hippocampal areas with elevated c-fos activation and increased cell death. Long-term induction of Notch-2 also occurred in CA1 and CA3 in and around areas of cell death, and had a distinct pattern of expression as compared to Notch-1. In vitro oxygen glucose deprivation treatment showed a similar increase in Notch-2 in apoptotic cells. In vitro gain of function experiments, using an active form of Notch-2, show that Notch-2 induction is neurotoxic to a comparable extent as oxygen glucose deprivation treatment.
These results suggest that Notch-2 up-regulation after neonatal ischemia is detrimental to neuronal survival.
Notch 受体（1-4）是膜蛋白，在配体刺激下，其胞质结构域释放出来作为转录因子。Notch-2 在发育和癌症过程中均促进增殖，但它在缺血性损伤中的作用还不太清楚。本研究的目的是了解新生儿卒中后是否会诱导 Notch-2，并研究其功能相关性。
将 P12 CD1 小鼠进行永久性单侧（右侧）颈总动脉双重结扎。
新生鼠缺血导致进行性脑损伤，伴有凋亡延长和 Notch-2 上调。损伤后，Notch-2 在海马区表达上调，c-fos 激活增加，细胞死亡增加。Notch-2 的长期诱导也发生在 CA1 和 CA3 区以及细胞死亡区域周围，与 Notch-1 的表达模式明显不同。体外氧葡萄糖剥夺处理显示凋亡细胞中 Notch-2 增加相似。体外功能获得实验表明，Notch-2 的诱导对神经元具有与氧葡萄糖剥夺处理相当的神经毒性。
这些结果表明，新生鼠缺血后 Notch-2 的上调对神经元存活有害。
