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.

Public Health Relevance

Pediatric cardiac arrest is a significant public health problem, with high mortality and morbidity. A majority of children surviving cardiac arrest are left with neurological impairment, underscoring the need for innovative therapeutic strategies aimed at improving the quality of life after pediatric cardiac arrest. This project will elucidate mechanism of cerebral blood flow disturbances and neurotoxicity after pediatric cardiac arrest, and will use dual vascular- and neuronal- therapies with the goal of reducing neuronal damage and improving neurological outcome after pediatric cardiac arrest.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD075760-02
Application #
8731962
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Maholmes, Valerie
Project Start
2013-09-10
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$303,268
Indirect Cost
$101,578
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Manole, Mioara D; Kochanek, Patrick M; Bayýýr, Hulya et al. (2014) Brain tissue oxygen monitoring identifies cortical hypoxia and thalamic hyperoxia after experimental cardiac arrest in rats. Pediatr Res 75:295-301
Drabek, Tomas; Foley, Lesley M; Janata, Andreas et al. (2014) Global and regional differences in cerebral blood flow after asphyxial versus ventricular fibrillation cardiac arrest in rats using ASL-MRI. Resuscitation 85:964-71
Shaik, Jafar Sadik B; Miller, Tricia M; Graham, Steven H et al. (2014) Rapid and simultaneous quantitation of prostanoids by UPLC-MS/MS in rat brain. J Chromatogr B Analyt Technol Biomed Life Sci 945-946:207-16
Tress, Erika E; Clark, Robert S B; Foley, Lesley M et al. (2014) Blood brain barrier is impermeable to solutes and permeable to water after experimental pediatric cardiac arrest. Neurosci Lett 578:17-21