CLINICAL APPLICATIONS OF NEUROGENESIS FOR THE TREATMENT OF ISCHEMIC CEREBROVASCULAR DISEASE

点击翻译按钮获取中文摘要

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