Certain cells undergo apoptosis within twenty-four hours after XRT, including oligodendrocytes (6, 7, 40), subependymal cells (which surround the ventricles of the brain and may include cells with properties of neural stem cells) (5, 41–43), certain neurons (4), and endothelial cells (3, 8). Neural precursor cells of the hippocampal dentate gyrus also are radiosensitive and undergo apoptosis within the first twenty-four hours after XRT (4). In rat spinal cord, we have shown that some of the apoptotic oligodendroglial cells have the phenotype of oligodendroglial precursors (unpublished data).
RADIATION-INDUCED APOPTOSIS OF ENDOTHELIAL CELLS
A 15% decrease in the number of endothelial cells in rat brain was documented twenty-four hours following a single X-ray dose of 25 Gy (44). A dose-dependent loss of endothelial cells at twentyfour hours was also observed in rat spinal cord after XRT (45). These findings are consistent with the observation of a peak of endothelial apoptosis at twelve hours in the rodent CNS post-XRT (3). Importantly, whereas oligodendrocyte apoptosis after XRT is p53-dependent (5), endothelial cell apoptosis is not p53-dependent. Radiation-induced endothelial cell apoptosis is mediated by the second messenger ceramide, which is generated from sphingomyelin following activation of sphingomyelinases (46). Thus, consistent with the notion that radiation-induced endothelial apoptosis in the CNS is mediated by the acid sphingomyelinase (ASMase) pathway, endothelial apoptosis after XRT was reduced in the CNS of ASMase knockout animals (3, 8).
Acute disruption of the BBB is well recognized after XRT of the CNS (45, 47–49). The dependence of radiation-induced endothelial apoptosis on the ASMase pathway provides a genetic approach to determine the role of endothelial cell apoptosis in acute BBB breakdown following XRT. Following a single dose of 50 Gy to the spinal cord, endothelial density was reduced by almost 50%, and disruption of the blood–spinal cord barrier (BSCB) was observed in ASMase wild-type mice, but not in ASMase-knockout animals (8). Both p53 wild-type and knockout mice exhibited a similar reduction in endothelial cell numbers and BSCB disruption after spinal cord XRT. These data provide compelling evidence that apoptosis of endothelial cells initiates acute BBB disruption in the CNS after XRT. One therapeutic implication is that targeting endothelial apoptosis may be a neuroprotective strategy against acute BBB disruption after XRT. As for early changes in gene expression, the relationship between early endothelial cell death and tissue injury that appears months later is not known.
RADIATION-INDUCED OLIGODENDROGLIAL APOPTOSIS
In the irradiated spinal cord, a reduction of oligodendrocytes twenty-four hours after XRT is observed (6, 40). At two to four weeks after XRT, there is a dramatic loss of oligodendroglial progenitor cells in rat spinal cord (50). After XRT of the rat cervical spinal cord with 15 or 23 Gy of 6 MeV photons, the clonogenic oligodendrocyte progenitor cell pool is reduced to less than 0.1% of its normal population, followed by a dose-dependent recovery, reaching a maximum of 40–80% of control values at three months post-XRT. Only after the paralytic dose of 23 Gy does a secondary decline of oligodendrocyte progenitors occur, between four and five months post-XRT (51).
Our recent data (unpublished) shows that loss of oligodendroglial progenitor cells was accompanied by glial proliferation. Proliferative cells have the phenotype of oligodendroglial progenitor cells. Early proliferation of oligodendroglial progenitor cells however was not impaired in the irradiated spinal cord of p53- knockout mice. Given the dependence of radiation-induced apoptosis of oligodendroglial cells on p53, this suggests that the early proliferation of oligodendroglial progenitors observed may not be linked directly to apoptosis of mature oligodendrocytes.
A number of early events, such as oligodendroglial apoptosis, reduced oligodendroglial density, and changes in oligodendroglial gene expression, were seen in the irradiated rodent spinal cord. These events were observed after a myelopathic dose of 22 Gy, and similar changes were observed after a much lower dose of 8 Gy. The relevance of early oligodendroglial apoptosis to late demyelination remains uncertain. These findings however suggest that these early events may not be directly associated with the late demyelination observed after XRT (40).
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