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Hypoxia-ischemia (HI) is a leading cause of white matter damage, a major contributor to cerebral palsy in premature infants. Preferential white matter damage is believed to result from vulnerability of the immature oligodendrocyte (the pro-OL) to factors elevated during ischemic damage, such as oxygen free radicals and glutamate. In order to determine whether pro-OLs undergo apoptotic death after HI, we analyzed periventricular white matter OLs in P7 rats 4, 12 and 24 h after HI to analyze the time course and mode of cell death. DNA fragmentation was seen at 12 and 24 h of recovery after HI, representing a 17-fold increase over control. In addition, caspase-3 activation was found in NG2+ pro-OLs at 12 h. Electron-microscopic analysis of cell death in the white matter revealed a transition from early necrotic deaths to hybrid cell deaths to classical apoptosis between 4 and 24 h of recovery from HI. The delayed time course of apoptosis in pro-OLs supports the feasibility of interventions to improve clinical outcomes for newborns surviving birth asphyxia.

Oligodendroglial death due to overactivation of the AMPA/kainate glutamate receptors is implicated in white matter damage in multiple CNS disorders. We previously demonstrated that glutamate induces caspase-3 activation and death of the late oligodendrocyte progenitor known as the pro-oligodendroblast (pro-OL) via activation of the AMPA/kainate glutamate receptors. We also demonstrated that IGF-I had the unique ability to sustain activation of Akt in the pro-OL and provide long-term protection of these cells from glutamate-mediated apoptosis. The goal of these studies was to investigate the mechanisms of glutamate toxicity and IGF-I-mediated survival in the pro-OL. IGF-I prevented glutamate-induced loss of mitochondrial membrane potential, cytochrome c release, and caspase-9 activation. In contrast to IGF-I mediated survival mechanisms in neurons, IGF-I had no effect on the influx or recovery of intracellular calcium levels or on levels of major pro- and anti-apoptotic molecules including Bax or Bcl-xL. Rather, IGF-I prevented the glutamate-induced translocation of Bax to the mitochondria. Moreover, IGF-I prevented caspase-3 activation in pro-OLs as long as 8 h after exposure of the cells to glutamate, suggesting that delayed activation of IGF-I-mediated survival pathways can block glutamate-mediated apoptosis in pro-OLs. The results of these experiments define the mechanisms by which glutamate kills oligodendrocyte progenitor cells and by which IGF-I blocks glutamate-induced apoptosis in these cells. The data also demonstrate that IGF-I disrupts the glutamate-mediated apoptotic pathway in the pro-OL through mechanisms that are distinct from its survival-promoting actions in neurons.

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