Periventricular leukomalacia (PVL) is a form of white matter disease found in about 10% of premature infants with very low birth weight (less than 1500 grams), and is frequently associated with severe neurological disorders such as cerebral palsy and mental retardation. With improved perinatal care, more preterm infants survive, but the incidence of PVL in these infants has not been reduced. Hypoxia-ischemia (HI) has been considered as the primary cause for PVL. In the past, however, more attention has been paid to HI-induced neuronal injury, while HI-induced white matter injury has received less attention. Existing data suggest that occurrence of PVL is possibly associated with susceptibility of oligodendrocytes (OLs) to HI insults at a particular maturation stage. Chronic ischemia achieved through bilateral carotid artery occlusion combined with a short term hypoxic exposure (BCAO+H) in neonatal rats has been found to induce preferential white matter injury resembling the injury found in the infant brain with PVL. The objective of this study is to use this model to investigate mechanisms involved in PVL-like white matter injury and provide necessary information leading to protection of the brain of preterm infants from white matter damage. The preliminary data presented in this proposal indicate that the preferential white matter injury induced by BCAO+H is associated with increased microglial activation, astrogliosis and increased expression of inflammatory cytokines in the neonatal rat brain. The injury is also concomitant with decreased number of immature OLs and abnormalities in expression of myelin basic protein in the rat brain. The proposed study will examine roles of inflammatory cytokines in mediating injuries to OLs at specific maturation stages, the putative target cells of PVL-like brain injury. Following the BCAO+H procedure performed in neonatal rats at different postnatal days, when OLs in these rat brains are at different maturation stages, brain injury and induction of inflammatory cytokines in the rat brain will be examined. A double-labeling technique will be used to identify cytokine-expressing cells. Effectiveness of treatment with tetracycline's, cytokine antibodies or binding proteins in attenuation of white matter injury and in improvement of neurobehavioral performance in rats will also be examined in vivo. Direct effects of inflammatory cytokines and IGF-1 on survival and differentiation of OLs will be examined in cultures of OLs at various maturation stages.
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