Apoptosis is a morphologically defined form of programmed cell death seen in a variety of circumstances, including immune cell selection, carcinogenesis and development. Apoptosis has very recently been seen after ischemic or traumatic injury to the central nervous system (CNS), suggesting that active cell death as well as passive necrosis may mediate damage after CNS injury. After spinal cord injury (SCI) in the rat, typical post-traumatic necrosis occurred, but in addition, apoptotic cells were found from 6 hours to 3 weeks after injury, especially in the spinal white matter. Apoptotic cells were positive for oligodendrocyte markers. After SCI in monkeys, apoptotic cells were found within remote degenerating fiber tracts. Both secondary degeneration at the site of SCI and the chronic demyelination of tracts away from the injury appear to be due in part to apoptosis. As cytokines have been shown to mediate oligodendrocyte death in vitro, it seems likely that chronic demyelination after CNS injury shares features with chronic degenerative disorders like multiple sclerosis.

Following spinal cord contusion in the rat, apoptosis has been observed in the white matter for long distances remote from the center of the lesion and is primarily associated with degenerating fiber tracts. We have previously reported that many of the apoptotic cells are oligodendrocytes. Here we show that the oligodendrocyte death is maximal at 8 days postinjury and suggest that loss of oligodendrocytes may result in demyelination of axons that have survived the initial trauma. There are two mechanisms that may account for the observed oligodendrocyte apoptosis. The apoptotic cell death may result from the loss of trophic support after axonal degeneration or it may be the consequence of microglial activation. The hypothesis that oligodendrocyte apoptosis is secondary to microglial activation is supported by our observations of microglia with an activated morphology in the same regions as apoptosis and apparent contact between some of the apoptotic oligodendrocytes and microglial processes. In addition to oligodendrocyte apoptosis, a subpopulation of microglia appears to be susceptible to apoptotic cell death as well, as evidenced by the presence of apoptotic bodies in OX42 immunopositive profiles. Thus, the population of apoptotic cells following spinal cord contusion is comprised of oligodendrocytes and putative phagocytic microglia or macrophages. Given the delayed time course of oligodendrocyte death, the apoptotic death of oligodendrocytes may be amenable to pharmacological intervention with subsequent improvement in functional recovery.

Apoptosis is the morphological counterpart of active, genetically programmed cell death and is important in development, immune function, and carcinogenesis. Recent data suggest that apoptosis may be important in neurodegenerative disorders, ischemic brain injury, and neurotrauma as well. Here we review very recent data from our laboratory and others that show that at least some of the pronounced secondary injury that follows spinal cord injury (SCI) may be caused by apoptosis and associated intracellular death pathways. Both neurons and glia seem to die by apoptosis; the response of oligodendrocytes in long tracts undergoing Wallerian degeneration is particularly long lived and may be responsible for chronic demyelination and some of the dysfunction in chronic SCI. These findings suggest that the therapeutic window for treatment of acute SCI may extend into the chronic phase. In addition, proliferation of ependymal cells occurs in concert with cell death, suggesting that both degeneration and repair may occur at the same time. Therapies aimed at altering the balance between these cellular events may be useful for future treatments of SCI. NEURO-SCIENTIST 4:163-171, 1998