Perinatal hypoxia ischemia (H-I) brain damage is an important risk factor for acquired disabilities in children. Brain damage from H-I is a main cause of motor impairments such as those found in cerebral palsy and dystonia. The costs to society are huge, because of loss of potential productivity and the burden on the individual, family and social institutions, starting at birth and lasting an entire lifetime. Comparatively, CP has a highr index of burden of disease than many neurodegenerative diseases affecting the twilight years of life. There is a paucity of therapies available for fetal H-I. With the availability of a clinicall applicable animal model of cerebral palsy, innovative methods of investigating free radical damage and the integration of new non- invasive markers of injury a unique opportunity arises to systematically investigate the mechanisms of the developing fetal brain to H-I. Tetrahydrobiopterin (BH4) is an important cofactor in normal development of brain function. Deficiency of BH4 is also associated with development of motor disabilities. Our previous research has identified that motor deficits observed in the animal model is dependent on critical BH4 deficiency in different parts of the brain. Treatment of fetal brain with BH4 prior to H-I before birth significantly decreases motor deficits observed after birth. Thus we propose that development of motor deficits can be explained by a double-hit model, H-I in combination with developmentally low BH4. We hypothesize that the BH4 pathway in immature brain is selectively disrupted by hypoxia-ischemia injury leading to development of motor deficits. This hypothesis will be tested in fetal rabbits subjected to in utero H-I injury in the prenatal period. Using this model we will (1) elucidate if there is a threshold for BH4 concentration causing critical fetal brain injury;(2) investigate if the regional biosynthetic deficits of BH4 in neuron determines the development of motor deficits after H-I;(3) elucidate if BH4 treatment acts through a mechanism that involves oxidation- reduction. The influence of BH4 in the brain responses will be assessed by using state-of-the-art analytical methodologies to characterize BH4, and BH4 synthetic pathway changes in the immature brain. Additionally magnetic resonance imaging analysis will help in the identification of at-risk fetuses for neurobehavioral deficits. The successful completion of this work will hopefully bridge the gap in knowledge between the mechanisms of fetal brain injury and in broadening the potential application of BH4 therapies in the prevention and improvement of movement disorders in children.

Public Health Relevance

There is a paucity of effective treatments for cerebral palsy and this proposal tests a promising strategy aimed at a preventive cure for this disease. The proposed studies tests the ways at which a vitamin-like co- factor is involved in brain injury. Using surrogate markers of magnetic resonance imaging this proposal will study what happens to brain cells in the early critical phase of injury, which seems to determine the eventual course of events leading to movement disorders of cerebral palsy.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Koenig, James I
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Northshore University Healthsystem
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Yu, Lei; Vasquez-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