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OBJECTIVE To design a new class of selective neuronal nitric oxide synthase (NOS) inhibitors, and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxia-ischemia-induced deaths and reduces the number of newborn kits exhibiting signs of CP. METHODS We used a novel computer-based drug design method called fragment hopping(More)
Disruption of oligodendrocyte lineage progression is implicated in the white-matter injury that occurs in cerebral palsy. We have previously published a model in rabbits consistent with cerebral palsy. Little is known of normal white-matter development in perinatal rabbits. Using a multidimensional approach, we defined the relationship of oligodendrocyte(More)
OBJECTIVE Tetrahydrobiopterin (BH(4)) deficiency is a cause of dystonia at birth. We hypothesized that BH(4) is a developmental factor determining vulnerability of the immature fetal brain to hypoxic-ischemic injury and subsequent motor deficits in newborns. METHODS Pregnant rabbits were subjected to 40-minute uterine ischemia, and fetal brains were(More)
The objective of the study was to assess predictive value of serial diffusion tensor MRI (DTI) for the white matter injury and neurodevelopmental outcome in a cohort of premature infants. Twenty-four infants less than 32 weeks' gestation were stratified to a control group (n = 11), mild brain injury with grades 1-2 of intraventricular hemorrhage (n = 6) and(More)
Disorders of the maternal-placental-fetal unit often results in fetal brain injury, which in turn results in one of the highest burdens of disease, because of the lifelong consequences and cost to society. Investigating hypoxia-ischemia in the perinatal period requires the factoring of timing of the insult, determination of end-points, taking into account(More)
Perinatal brain injury results in one of the highest burdens of disease in view of the lifelong consequences and is of enormous cost to society. This makes it imperative to develop better animal models that mimic the human condition. Many neurodevelopmental deficits, such as cerebral palsy, are believed to be a result of prenatal hypoxia-ischemia in humans.(More)
Perinatal hypoxic-ischemic brain injury remains a major cause of cerebral palsy. Although therapeutic hypothermia is now established to improve recovery from hypoxia-ischemia (HI) at term, many infants continue to survive with disability, and hypothermia has not yet been tested in preterm infants. There is increasing evidence from in vitro and in vivo(More)
Hypertonia and postural deficits are observed in cerebral palsy and similar abnormalities are observed in postnatal rabbits after antenatal hypoxia-ischemia. To explain why some kits become hypertonic, we hypothesized that white matter injury was responsible for the hypertonia. We compared newborn kits at postnatal day 1 (P1) with and without hypertonia(More)
Prenatal hypoxia-ischemia to the developing brain has been strongly implicated in the subsequent development of the hypertonic motor deficits of cerebral palsy (CP) in premature and full-term infants who present with neonatal encephalopathy. Despite the enormous impact of CP, there is no animal model that reproduces the hypertonia and motor disturbances of(More)
Neuronal nitric oxide synthase (nNOS) and nitric oxide (NO) are implicated in neuronal injury following acute hypoxia-ischemia (HI). Our hypothesis was that NO from nNOS is responsible for ongoing mitochondrial dysfunction in near-term fetal HI. Recently, we synthesized new selective nNOS inhibitors that prevent the cerebral palsy phenotype in our animal(More)