Enhancement of Neurogenesis by Progenitor Cells as a Target for Gene Therapy in Cerebral Ischemia

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We evaluated proliferation of neural progenitors and neurogenesis in the subgranular zone (SGZ) of hippocampal dentate and subventricular zone (SVZ) in transient forebrain and focal ischemia. The number of proliferating cells in the SGZ reached a peek a week after ischemia, and proliferating cells represented the neuronal phenotype 4 weeks after bromodeoxyuridine labeling. The number of proliferating cells in the SVZ also increased after focal cerebral ischemia. However, differential expression of selective markers for neural stem/progenitor cells, Musashil(Msil) and nestin, was observed in both regions. Both Msil and nestin were impressed in neural progenitors in SVZ, however, only Msil was observed in progenitors in SGZ. Thereafter, we examined the involvement of cyclooxygenase-2 (COX2) on induced proliferation of neural progenitors after ischemia by using COX-2 selective inhibitor, NS398, and COX-2 knockout mice. Because induction of COX-2 protein was observed in neuron and astrocytes, but not in neural progenitors, prostaglandin may be involved in increased neurogenesis after ischemia. Our results demonstrated that proliferation of neural progenitors and neurogenesis after ischemia can be modified by modulation of COX-2. COX-2 may be a potential target of gene therapy for enhancing neurogenesis