Birth defects of the heart and circulatory system affect more infants than any other type of birth defect. Of all infants born each year, approximately 1 in 115 has heart and/or circulatory defects and most of them require cardiopulmonary bypass surgery. Despite remarkable advances in surgery, a substantial fraction of these patients manifest neurological and developmental abnormalities. The cellular and molecular mechanisms of neurologic injury in the newborn brain, associated with DHCA, are poorly understood. In proposed studies, oxygen dependent quenching of phosphorescence, a noninvasive optical method for measuring oxygen developed in our laboratory, will be used to measure the oxygen in the microvasculature of the brain of newborn piglets. This method allows for the first time continuous evaluation of the status of tissue oxygenation DHCA and post-arrest recovery. The oxygen histograms will be coupled with measurements of the blood flow, status of brain metabolism and the extent of brain injury. Our study will determine the dopamine dependent mechanisms of neuronal injury within the striatum. We will also evaluate some promising approaches in the protection of the brain from neuronal injury caused by DHCA. This proposal has two major goals: (a) To determine the role of dopamine and dopamine dependent biochemical and molecular alterations on striatal injury following circulatory arrest. (b) To identify potential strategies for neural protection, particularly in striatum, following circulatory arrest. To achieve these goals, we will test the following specific aims: 1. Hypoxia induced increase in extracellular levels of dopamine in the striatum during DHCA is a major contributor of neuronal injury in the striatum of newborn piglets. 2. Dopamine exerts a neurotoxic effect in striatum of newborn piglets by increasing production of free radicals during post-arrest period. 3. Increased extracellular dopamine in the striatum, acting through the D1 and D2 receptors, alters a cascade of key regulatory processes that contribute substantially to neuronal injury induced by DHCA. 4. During DHCA, brain oxygen deficiency results in a massive increase in extracellular dopamine and brain injury, and this can be prevented by selective cerebral perfusion (SCP). 5. Dopamine dependent striatal injury from prolonged periods of DHCA can be decreased with intermittent brief rescue periods of LFCPB.
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