Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Brain Res. 2010 Apr 23;1327:91-102. doi: 10.1016/j.brainres.2010.02.030. Epub 2010 Feb 19.
Convincing evidence has shown that brain ischemia causes the proliferation of neural stem cells/neural progenitor cells (NSCs/NPCs) in both the subventricular zone (SVZ) and the subgranular zone (SGZ) of adult brain. The role of brain ischemia-induced NSC/NPC proliferation, however, has remained unclear. Here we have determined whether brain ischemia-induced amplification of the NSCs/NPCs in adult brain is required for brain self-protection. The approach of intracerebroventricular (ICV) infusion of cytosine arabinoside (Ara-C), an inhibitor for cell proliferation, for the first 7days after brain ischemia was used to block ischemia-induced NSC/NPC proliferation. We observed that ICV infusion of Ara-C caused a complete blockade of NSC/NPC proliferation in the SVZ and a dramatic reduction of NSC/NPC proliferation in the SGZ. Additionally, as a result of the inhibition of ischemia-induced NSC/NPC pool amplification, the number of neurons in the hippocampal CA1 and CA3 was significantly reduced, the infarction size was significantly enlarged, and neurological deficits were significantly worsened after focal brain ischemia. We also found that an NSC/NPC-conditioned medium showed neuroprotective effects in vitro and that adult NSC/NPC-released brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are required for NSC/NPC-conditioned medium-induced neuroprotection. These data suggest that NSC/NPC-generated trophic factors are neuroprotective and that brain ischemia-triggered NSC/NPC proliferation is crucial for brain protection. This study provides insights into the contribution of endogenous NSCs/NPCs to brain self-protection in adult brain after ischemia injury.
已有确凿证据表明，脑缺血会导致成年大脑的侧脑室下区（SVZ）和颗粒下区（SGZ）中神经干细胞/神经前体细胞（NSCs/NPCs）的增殖。然而，脑缺血诱导的 NSCs/NPC 增殖的作用尚不清楚。在这里，我们确定了成年大脑中脑缺血诱导的 NSCs/NPC 扩增是否是大脑自我保护所必需的。通过向脑缺血后第 7 天的侧脑室（ICV）输注细胞增殖抑制剂阿糖胞苷（Ara-C），我们观察到 ICV 输注 Ara-C 会完全阻断 SVZ 中的 NSCs/NPC 增殖，并显著减少 SGZ 中的 NSCs/NPC 增殖。此外，由于抑制了缺血诱导的 NSCs/NPC 池扩增，海马 CA1 和 CA3 中的神经元数量显著减少，梗死面积显著增大，局灶性脑缺血后的神经功能缺损明显加重。我们还发现 NSCs/NPC 条件培养基在体外具有神经保护作用，而成年 NSCs/NPC 释放的脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）是 NSCs/NPC 条件培养基诱导的神经保护所必需的。这些数据表明，NSCs/NPC 产生的营养因子具有神经保护作用，而脑缺血触发的 NSCs/NPC 增殖对大脑保护至关重要。这项研究为理解内源性 NSCs/NPC 在成年大脑缺血损伤后的自我保护中所起的作用提供了新的视角。
