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大鼠海马区神经发生增加，但缺血后神经发生增加的分子机制尚不清楚。这一发现表明，刺激并不是对祖细胞的缺血性侮辱，而是一种对祖细胞的缺血性伤害。在海马齿状回颗粒下带(SGZ)，溴脱氧尿嘧啶核苷(BrdU)阳性细胞数在缺血7d后增加了近6倍。超过80%的新生细胞表达神经干/祖细胞的标志物Musashi1(Msi1)。成年大鼠短暂性前脑缺血后，海马区反应性星形胶质细胞表达Msi1和Nestin，尤其是CA1区，直至35d，提示反应性星形胶质细胞可能具有幼稚特征。在海马DG的SGZ，MSI1和BrdU阳性细胞与…形成簇更严重的是脑缺血。相比之下，BrdU标记的巢蛋白阳性细胞很少。给予BrdU后28d，BrdU阳性细胞数明显减少，但仍高于对照组。然而，在对侧大脑半球的其他区域，包括吻侧脑室下区，BrdU阳性细胞的数量保持不变。这些结果表明，局灶性缺血刺激了神经元前体细胞的增殖，但不支持对侧海马区新生细胞的存活。环氧合酶(COX)-2是大脑中的主要同工酶，调节炎症、谷氨酸介导的细胞毒性和突触可塑性。我们发现，不同种类的COX抑制剂延迟治疗可显著抑制缺血后神经前体细胞对DG增殖的促进作用。在DG的神经元和星形胶质细胞中均有COX-2免疫反应，而在SGZ的神经前体细胞中未见COX-2免疫反应。此外，在杂合子和纯合子COX-2基因敲除小鼠的缺血后DG中，增殖的溴脱氧尿苷阳性细胞显著少于野生型小鼠。这些结果表明，COX-2是促进缺血后神经前体细胞增殖的重要调节剂。较少

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