Perinatal asphyxia remains a significant problem, accounting for 23% of neonatal deaths world wide. Up to 60% of survivors are left with life-long neurodevelopmental handicaps that include mental retardation, cerebral palsy, seizures and learning disabilities. Effective treatment strategies are currently limited. Recombinant erythropoietin (rEpo) is an effective neuroprotective agent, improving both short and long term neurologic outcome following brain injury in neonatal and adult animal models. Hypothermia is another promising treatment for perinatal asphyxia, improving outcomes for infants with mild and moderate hypoxic ischemic encephalopathy (HIE), but not severe HIE. Unfortunately, neither rEpo nor hypothermia alone provides complete neuroprotection. Our goal is to develop a safe and effective treatment for perinatal asphyxia that will decrease the subsequent neurologic injury, thereby helping affected children achieve their full potential and lead healthy and productive lives. We hypothesize that both rEpo and hypothermia will decrease the neurodevelopmental and structural consequences of perinatal asphyxia in near term pigtailed macaques (Macaca nemestrina), but that combined therapy with rEpo and hypothermia will provide even greater benefit. We have established a primate model of perinatal asphyxia which is ideal for preclinical evaluation of a combined neuroprotective treatment strategy under conditions that closely resemble human neonatal emergencies. We will utilize this model to test the following specific aims:
Aim 1) To determine which therapeutic strategy is most effective in decreasing the neurodevelopmental sequelae of perinatal asphyxia in near-term M. nemestrina: rEpo alone, hypothermia alone, or rEpo plus hypothermia (vs. vehicle controls);
Aim 2) To determine which therapeutic strategy is most effective in decreasing the structural consequences of perinatal asphyxia in brains of near-term M. nemestrina: rEpo alone, hypothermia alone, or rEpo plus hypothermia (vs. vehicle controls);
Aim 3) To establish the safety of high dose rEpo treatment, hypothermia, and rEpo plus head cooling in near-term M. nemestrina exposed to perinatal asphyxia. Evaluation will include EEG, cerebral function monitoring, MRI/MRS, neurobehavioral evaluations, biochemical and immunohistochemical studies. Several mechanisms of neuroprotection will be tested: 1) rEpo ? hypothermia will protect neurons from death, resulting in more neurons present at 9 months of age 2) rEpo will stimulate neurogenesis, resulting in more new neurons (BrdU labeled) present at 9 months of age, 3) rEpo and hypothermia will decrease inflammation, and 4) rEpo will increase iron utilization, thereby decreasing oxidative injury. This work will produce important data with direct clinical application to perinatal asphyxia, and possibly to other mechanisms of brain injury in infants and children.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD052820-05
Application #
8109928
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Parisi, Melissa
Project Start
2007-09-17
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$719,764
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Juul, Sandra E (2013) Hypothermia plus erythropoietin for neonatal neuroprotection? Commentary on Fan et al. and Fang et al. Pediatr Res 73:10-1
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Mann, Paul C; Woodrum, David E; Wilfond, Benjamin S (2013) Fuzzy images: Ethical implications of using routine neuroimaging in premature neonates to predict neurologic outcomes. J Pediatr 163:587-92
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Jacobson Misbe, Elizabeth N; Richards, Todd L; McPherson, Ronald J et al. (2011) Perinatal asphyxia in a nonhuman primate model. Dev Neurosci 33:210-21

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