White matter disease, periventricular leukomalacia (PVL) in particular, is a common form of brain injury in very preterm infants, and is frequently associated with severe neurological disorders such as cerebral palsy and cognitive impairment. PVL remains a major problem in preterm infants. Although it has been proposed that maternal or placental infection may contribute to PVL and that inflammatory cytokines are mediators between maternal infection and offspring brain white matter injury, the details of how maternal infection can cause white matter lesions in the infant brain are still poorly understood. The long-term objective of this study is to enhance our understanding of mechanisms involved in PVL and provide necessary information leading to protection of the preterm infant brain from white matter damage. Our preliminary data indicates that intracerebral administration of lipopolysaccharide (LPS), an endotoxin responsible for most of the inflammatory effects of infection from Gram-negative bacteria, increases inflammatory cytokine expression in the neonatal rat brain, causes brain injury resembling that seen in preterm infants with PVL, and results in neurological and learning behavioral alterations. Using this rat model, 4 hypotheses will be examined in the proposed studies: 1). Direct exposure of the neonatal rat brain to inflammatory cytokines or their combinations (IL1b, TNFa and IL-6), via intracerebral injection, may cause brain white matter injury, especially to developing oligodendrocytes; 2). Inhibition of microglial activation by minocycline, a tetracycline derivative, may reduce LPS induced oxidative and nitrosative stress in the neonatal rat brain and attenuate LPS-induced brain injury; 3). Application of alpha-pheny-N-tert-butyl-nitrorie (PBN), a free radical scavenger, may protect the immature brain from LPS-induced injury; and 4). Exogenous insulin-like growth factor-1 may protect oligodendrocytes from LPS-induced injury in vivo and in vitro. The results should further reveal the role of microglial activation and inflammatory cytokines in mediating LPS-induced brain injury and will also reveal the possibility of using microglial activation inhibitors or antioxidants as a potential therapeutic treatment for neonatal white matter lesions such as PVL.
Showing the most recent 10 out of 29 publications
