CYP 450-mediated CBF Dysregulation and Neurotoxicity in Pediatric Cardiac Arrest

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DESCRIPTION (provided by applicant): Pediatric cardiac arrest remains a significant cause of mortality and morbidity and thus it is an important public health problem. Hypoxic ischemic encephalopathy is the limiting factor for intact neurological recovery in a majority of pediatric patients after cardiac arrest. Cerebral blood flow disturbances may further contribute to neuropathological damage after cardiac arrest and represent an important target for novel therapies. Our long term research goal is to elucidate key vascular pathways involved in pathologic cerebral blood flow dysregulation after pediatric asphyxial cardiac arrest and to develop therapeutic strategies that prevent cerebral blood flow dysregulation and secondary neuronal damage. Compelling preliminary data suggest that the balance of vasoconstrictive and vasodilator eicosanoid metabolites of cytochrome P450 is disturbed in favor of vasoconstrictors after experimental pediatric cardiac asphyxial arrest. Furthermore, inhibiting the production of vasoconstrictive eicosanoids prevented the cortical hypoperfusion and improved neurological outcome in our pediatric asphyxial cardiac arrest model. The goal of this project is to elucidate mechanisms through which eicosanoid metabolites of cytochrome P450 4A/4F and 2C/2J produce cerebral blood flow dysregulation and neurotoxicity after pediatric cardiac arrest and to develop innovative therapies that target these pathways. We propose to 1) define the role of vasoconstrictor eicosanoids in cerebral blood flow dysregulation and neurodegeneration after pediatric cardiac arrest, 2) define the role of vasodilatatory eicosanoids in cerebral blood flow normalization and neuroprotection after pediatric cardiac arrest and 3) determine if inhibiting eicosanoid-induced vasoconstriction and enhancing eicosanoid- induced vasodilatation improves neurological outcome after pediatric cardiac arrest. We propose innovative approaches to assessing the neurovascular unit from both vascular and neuronal perspectives, from the molecular to the global level. We have assembled a collaborative team of experts in (i) mass spectrometry with expertise using a comprehensive lipidomic approach, (ii) cerebral blood flow assessment by arterial spin label magnetic resonance imaging, (iii) cell imaging for in vivo visualization of cortical microcirculation via two photon microscopy, and (iv) an outcome animal model of cardiac arrest. If these dual vascular- and neuronal-targeted therapies reduce secondary neuronal damage and improve outcome after pediatric asphyxial cardiac arrest, then clinical translation of this novel approach would be of significant impact for infants and children who suffer cardiac arrest.