Neonatal hypoxia often results in permanent CNS damage. Studies in our laboratory in 7 do rats exposed to 7-8% oxygen for 3h have demonstrated there is (1) a decrease in cortical thickness, without apparent necrosis, when brains are examined 7d later, (2) a decrease in seizure threshold at 70-90d, and that (3) these decreases can be prevented by dextromethorphan (DM, an NMDA-type glutamate receptor antagonist). We postulated that the cell loss due to pathologic programmed cell death (apoptosis) was responsible for the decreased cortical thickness. Brains were peρfusion-fixed at 3d and 7d post hypoxia and 8 μm paraffin sections were prepared. Tunel staining was carried out using a commercial kit (ApopTag; ONCOR, Gaithersburg, MD). Appropriate positive and negative controls were included. Slides were viewed by epifluorescence using standard fluorescein excitation and emission filters. At 7d following exposure, there was a significant increase (p<0.001) in the number of apoptotic cells in the cortex of animals exposed to hypoxia alone, when compared with normoxic animals. This effect was ameliorated in animals exposed to hypoxia, then treated with DM (p<0.01). In the small numbers of animals thus far, at 3d after exposure, there was a trend toward similar findings. Thus, mild-moderate hypoxic injury results in significant loss of cortical thickness by loss of cells via apoptosis. This effect is ameliorated with DM, an easily available and safe NMDA receptor antagonist. An understanding of the injury and the mechanisms leading up to cell death in mild-moderate hypoxia and the ability to use effective neuroprotective drugs after the hypoxic event could have far reaching therapeutic implications.Table

Table Number of apoptotic cells 3d and 7d after exposure in each of 4 experimental groups (mean+SEM,n).
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