CLINICAL APPLICATIONS OF NEUROGENESIS FOR THE TREATMENT OF ISCHEMIC CEREBROVASCULAR DISEASE

最近的研究表明，短暂性全脑缺血后，成年海马的神经发生增加；然而，缺血后神经发生增加的分子机制尚不清楚。发现祖细胞在缺血损伤后至少一周发生增殖，这表明刺激不是对祖细胞的缺血损伤。在海马齿状回亚颗粒区（SGZ），缺血7天后，溴脱氧尿苷（BrdU）阳性细胞的数量增加了约6倍。超过80%的新生细胞表达Musashi1 (Msi1)，这是一种神经干细胞/祖细胞的标志物。Msi1和nestin在成年大鼠短暂性前脑缺血后海马反应性星形胶质细胞中，尤其是CA1区被诱导至缺血后35 d，提示反应性星形胶质细胞可能具有未成熟特征。在海马DG的SGZ区，Msi1和brdu阳性细胞在缺血后形成簇状细胞。相比之下，很少巢阳性细胞被BrdU标记。缺血后给予BrdU 28天后，BrdU阳性细胞数量明显减少，但仍高于对照组。然而，在对侧半球的其他区域，包括吻侧室下区，brdu阳性细胞的数量保持不变。这些结果表明，局灶性缺血刺激了对侧海马神经元祖细胞的增殖，但不支持新生细胞的存活。环氧合酶(COX)-2是大脑中主要的同工酶，可调节炎症、谷氨酸介导的细胞毒性和突触可塑性。我们证明，延迟使用不同种类的COX抑制剂显著减弱了缺血后神经祖细胞DG增殖的增强。在DG的神经元和星形胶质细胞中均观察到COX-2免疫反应性，但在SGZ的神经祖细胞中未观察到。此外，在杂合和纯合COX-2敲除小鼠的遗传后DG中，溴脱氧尿嘧啶阳性细胞的增殖明显少于野生型小鼠。这些结果表明COX-2是促进缺血后神经祖细胞增殖的重要调节剂。少

Recent studies demonstrated that neurogenesis in the adult hippocampusincreased after transient global ischemia ; however, the molecular mechanism underlying increased neurogenesis after ischemia remains unclear. The finding that proliferation of progenitor cells occurred at least a week after ischemic insult suggests that the stimulus was not an ischemic insult to progenitor cells. In the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), the numbers of bromodeoxyuridine (BrdU)-positive cells increased approximately sixfold 7 days after ischemia. More than 80% of newborn cells expressed Musashi1 (Msi1), a marker of neural stem/progenitor cells. Msi1 and nestin were induced in the reactive astrocytes in the adult rat hippocampus after transient forebrain ischemia, especially in the CA1 region, until 35 days after ischemia, suggesting that reactive astrocytes might have immature characteristics. In the SGZ of the hippocampal DG, Msi1 and BrdU-positive cells formed clusters af … More ter ischemia. In contrast, very few nestinpositive cells were labeled by BrdU. The number of BrdU-positive cells markedly decreased 28 days after BrdU administration after ischemia, but it was still elevated compared with control. However, in the other areas of the contralateral hemisphere including the rostral subventricular zone, the number of BrdU-positive cells remained unchanged. These results showed that focal ischemia stimulated the proliferation of neuronal progenitor cells, but did not support survival of newborn cells in the contralateral hippocampus. Cyclooxygenase (COX)-2, the principal isoenzyme in the brain, modulates inflammation, glutamate-mediated cytotoxicity, and synaptic plasticity. We demonstrated that delayed treatment with different classes of COX inhibitor significantly blunted enhancement of DG proliferation of neural progenitor cells after ischemia. COX-2 immunoreactivity was observed in both neurons and astrocytes in the DG, but not in neural progenitor cells in the SGZ. Moreover, in the postischemic DG of heterozygous and homozygous COX-2 knockout mice, proliferating bromodeoxyuridine-positive cells were significantly fewer than in wild-type littermates. These results demonstrate that COX-2 is an important modulator in enhancement of proliferation of neural progenitor cells after ischemia. Less