Cerebral palsy (CP) is the leading cause of neurological disability in survivors of neonatal intensive care. The impediments to progress have been a lack of a suitable animal model of CP and a lack of diagnostic tools of fetal brain injury;both are addressed in this proposal. We will utilize a clinically relevant fetal animal mode mimicking acute placental insufficiency recently developed by us, which exhibits a CP phenotype in newborn rabbit pups following fetal hypoxia-ischemia (H-l) at 70% gestation. We have previously shown that reactive oxygen (ROS) and reactive nitrogen species (RNS) are produced in fetal brain after H-l in this model, and administration of antioxidants to the mother ameliorates fetal brain injury and reverses hypertonia. Pilot studies show that white matter (WM) injury accompanied by death of oligodendrocyte (OL) precursors is produced by the H-l insult. Our approach focuses on cellular and molecular determinants of preterm cerebral white matter injury and its sequelae and uses a multidisciplinary innovative approach, integrating recent advances in immunohistochemistry, flow cytometry, magnetic resonance imaging (MRI) electrophysiology, myelination and oxidant biochemistry. Our hypothesis is that the predilection of the preterm white matter to injury from H-l is related to a maturation-dependent vulnerability of OL precursors whose death is a pathogenic factor in the genesis of subsequent myelination disturbances. We will also test the hypothesis that the vulnerability of OL precursors to H-l is related to production of reactive oxygen and nitrogen species in fetal brain.
The specific aims are to determine: (1) whether neurobehavioral changes, specifically hypertonia at P1, induced by fetal H-l, are associated with white matter injury. (2) whether death of OL precursors from H-l is associated with subsequent injury to fiber tracts in the white matter. (3) the role of reactive oxygen and nitrogen species in OL precursor and white matter injury at premature gestation. Our objectives are to understand the factors that predispose OL precursors to death from H-l and to establish whether there is a causal relationship between OL death in vivo and the genesis of cerebral myelination disturbances. Upon completion of this project, we hope to gain insight into strategies to prevent white matter injury by understanding intrinsic features of the OL which influence susceptibility to H-l. Efficacy of better clinical and biochemical markers of white matter injury including non-invasive MRI measures and safe, non-toxic therapies aimed at the fetus but administered to the mother will be tested.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Morris, Jill A
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Northshore University Healthsystem
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Drobyshevsky, Alexander; Takada, Silvia Honda; Luo, Kehuan et al. (2015) Elevated spinal monoamine neurotransmitters after antenatal hypoxia-ischemia in rabbit cerebral palsy model. J Neurochem 132:394-402
Drobyshevsky, Alexander; Cotten, C Michael; Shi, Zhongjie et al. (2015) Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model. Dev Neurosci 37:349-62
Drobyshevsky, Alexander; Jiang, Rugang; Derrick, Matthew et al. (2014) Functional correlates of central white matter maturation in perinatal period in rabbits. Exp Neurol 261:76-86
Drobyshevsky, Alexander; Jiang, Rugang; Lin, Laixiang et al. (2014) Unmyelinated axon loss with postnatal hypertonia after fetal hypoxia. Ann Neurol 75:533-41
Yu, Lei; Vásquez-Vivar, Jeannette; Jiang, Rugang et al. (2014) Developmental susceptibility of neurons to transient tetrahydrobiopterin insufficiency and antenatal hypoxia-ischemia in fetal rabbits. Free Radic Biol Med 67:426-36
Drury, Paul P; Davidson, Joanne O; van den Heuij, Lotte G et al. (2013) Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep. Exp Neurol 250:282-92
Drobyshevsky, Alexander; Derrick, Matthew; Luo, Kehuan et al. (2012) Near-term fetal hypoxia-ischemia in rabbits: MRI can predict muscle tone abnormalities and deep brain injury. Stroke 43:2757-63
Drobyshevsky, Alexander; Luo, Kehuan; Derrick, Matthew et al. (2012) Motor deficits are triggered by reperfusion-reoxygenation injury as diagnosed by MRI and by a mechanism involving oxidants. J Neurosci 32:5500-9
Yu, Lei; Derrick, Matthew; Ji, Haitao et al. (2011) Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: comparison between JI-8 and 7-nitroindazole. Dev Neurosci 33:312-9
Buser, Joshua R; Segovia, Kristen N; Dean, Justin M et al. (2010) Timing of appearance of late oligodendrocyte progenitors coincides with enhanced susceptibility of preterm rabbit cerebral white matter to hypoxia-ischemia. J Cereb Blood Flow Metab 30:1053-65

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