Periventricular leukomalacia is the predominant form of brain injury in the premature infant. PVL is related to hypoxia-ischemia (H-I) and results in cerebral palsy, the leading cause of neurological disability in survivors of neonatal intensive care. Since the death of OL precursors could explain the myelination disturbances that are the major pathological feature of PVL, we developed a true fetal model to specifically examine the response of the rabbit cerebral white matter to H-I. White matter injury is produced by an insult that mimics acute placental insufficiency and is accompanied by death of OL precursors, suggesting an explanation for the developmental specificity of PVL. We will test the hypothesis that the predilection of the preterm white matter to injury from H-I is related to a maturation-dependent vulnerability of OL precursors whose death is pathogenic for subsequent myelination disturbances. Our approach is a significant departure from previous studies in that we will focus on cellular mechanisms of perinatal white matter injury. Hence, we will precisely define the relative susceptibility of successive stages in the OL lineage to death triggered by H-I with OL lineage-specific markers that have not been studied before. A multidisciplinary approach will be taken that integrates recent advances in immunohistochemistry, flow cytometry, magnetic resonance imaging and oxidant biochemistry to investigate the cellular and molecular determinants of preterm cerebral white matter injury and its sequelae. Our long-term objectives are to understand the factors that predispose OL precursors to death from H-I and to establish whether there is a causal relationship between OL death and genesis of cerebral myelination disturbances.
The specific aims are to determine: (1) Whether the susceptibility of rabbit OL precursors to H-I is maturation-dependent. (2) Whether death of OL precursors from H-I results in subsequent myelination disturbances. (3) The role of reactive oxygen and nitrogen species in preterm white matter injury. Upon completion of this project, we hope to gain insight into strategies to prevent PVL by understanding intrinsic features of the OL which influence susceptibility to H-I, by developing better clinical and biochemical markers of white matter injury, and by testing the efficacy of safe, non-toxic therapies aimed at the fetus but delivered via the mother.
