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Brain Res. 2005 Oct 5;1058(1-2):167-77. Epub 2005 Sep 2.

Ischemia-stimulated neurogenesis is regulated by proliferation, migration, differentiation and caspase activation of hippocampal precursor cells.

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Neuroscience Discovery Research, Wyeth Research, Princeton, NJ 08543-8000, USA.


A brief ischemic injury to the gerbil forebrain that caused selective damage in the CA1 region of the hippocampus also enhanced the production of new cells in the hippocampal neurogenic area. When evaluated 1 week after bromodeoxyuridine (BrdU) injection, approximately ten times more labeled cells were detected in the hippocampal dentate gyrus in ischemic animals than controls, indicating a stimulation of mitotic activity. To assess the temporal course of the survival and fate of these newborn cells, we monitored BrdU labeling and cell marker expression up to 60 days after ischemia (DAI). Loss of BrdU-positive cells was observed from both control and ischemic animals, but at 30 DAI and afterward, the ischemic group maintained more than 3 times as many BrdU-positive cells as the control group. In addition, ischemic injury also fostered the neuronal differentiation of these cells beyond the capacity observed in control animals and facilitated the migration of developing neurons to a neuronal cellular layer. The establishment of a temporal correlation between differentiation and migration provides evidence of the functional maturation of these cells. Surprisingly, we found that ischemic injury induced activation of caspase-3, not only in the CA1 region as expected, but also in the dentate subgranular zone (SGZ). Active caspase-3 immunoreactivity in the subgranular layer was co-localized with an early neuronal marker, suggesting that caspase-mediated apoptosis could mediate the loss of neurogenic cells in the SGZ. Inhibiting caspase-3 in the context of ischemia-induced neurogenesis might provide an opportunity for functional repair and a therapeutic outcome in the wake of ischemic injury.

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