Oxygen deficiency in babies results in dire consequences of stillbirths, newborn epilepsy, cerebral palsy, mental retardation and learning difficulties later in life. The emotional and monetary costs of these consequences to society are enormous. The long-term objectives are to find new ways of diagnosing and treating brain damage in a baby resulting from oxygen deficiency in the mother's womb. A versatile animal model in pregnant rabbits was developed that allows the study of different ages before birth and manipulation of different types of oxygen deficiency. Initial studies show that certain manipulations can result in baby rabbits behaving similarly to cerebral palsy patients. The proposal aims to study critical causes of baby brain injury from oxygen deficiency, such as production of a certain type of free radicals, called reactive nitrogen species. These are highly reactive chemicals originating from nitric oxide and superoxide. The main question asked in this proposal is whether the enzymes that produce nitric oxide or superoxide, called nitric oxide synthase and xanthine oxidase, are responsible for the injury to one specific brain cell type, neurons, in oxygen deficiency.
The Specific Aims are: 1) Determine the modality of hypoxia-ischemia and gestational age that causes neurobehavioral changes mimicking cerebral palsy, 2) Determine the role of reactive nitrogen species in fetal neuronal injury following hypoxia-ischemia at different gestational ages, and 3) Determine the role of neuronal nitric oxide synthase and xanthine oxidase in reactive nitrogen species-mediated neuronal injury caused by fetal hypoxia ischemia. New innovations proposed are the study of brain cell fate using tissue culture techniques and flow cytometry, use of behavior testing in rabbit babies, the study of live brain structures and state of neurons by magnetic resonance imaging, and new treatments for the reactive nitrogen species produced. These studies will result in a better understanding of the mechanisms of brain injury in babies and may result in the development of better diagnostic tools and treatments for babies at risk for brain injury from oxygen deficiency.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Hicks, Ramona R
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Northshore University Healthsystem
United States
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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
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
Derrick, Matthew; Englof, Ila; Drobyshevsky, Alexander et al. (2012) Intrauterine fetal demise can be remote from the inciting insult in an animal model of hypoxia-ischemia. Pediatr Res 72:154-60
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
Rao, Suma; Lin, Zhenlang; Drobyshevsky, Alexander et al. (2011) Involvement of neuronal nitric oxide synthase in ongoing fetal brain injury following near-term rabbit hypoxia-ischemia. Dev Neurosci 33:288-98

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