Cellular and molecular pathogenesis of periventricular white matter injury

Periventricular white matter injury has a high incidence, particularly in the premature infant. A prominent feature of the pathogenesis of this injury, which ultimately results in disrupted myelination of periventricular white matter tracts, is a loss of oligodendrocytes (OLs). The timing of injury corresponds to the period in white matter development when OL precursors predominate. This article focuses on current understanding of the cellular and molecular basis for the developmental vulnerability of OL precursors that may predispose to their loss in periventricular leukomalacia (PVL). Recent advances in the cellular neurobiology of OL development have permitted study of the processes that regulate survival of developing OLs. Several potentially complementary etiologies for the developmental vulnerability of OL precursors are reviewed: (1) free-radical-mediated toxicity in the setting of oxidative stress, (2) cytotoxic cytokines, and (3) a critical dependence on selected trophic factors during certain periods in OL development. Recent work indicates that these causes of cell death are mediated by a common mechanism involving apoptosis. Potential therapeutic interventions for interruption of the pathways mediating OL death are examined.