This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Perinatal asphyxia accounts for 23% of neonatal deaths globally. 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: Hypothermia has been shown to decrease brain injury, but only for mild and moderate asphyxia;recombinant erythropoietin (rEpo) improves both short and long term neurologic outcome following brain injury in animal models, but has not been tested in human infants. Neither treatment provides complete protection. 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), and that combined therapy with rEpo and hypothermia will provide even greater benefit. We will utilize a non-human primate model of perinatal asphyxia 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 hypothermia in near-term M. nemestrina exposed to perinatal asphyxia. 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.