Optimizing Neuroprotection Following Perinatal Asphyxia

描述（由申请人提供）：围产期窒息仍然是一个重大问题，占全世界新生儿死亡的23%。高达60%的幸存者留下终身神经发育障碍，包括智力迟钝、脑瘫、癫痫发作和学习障碍。目前有效的治疗策略有限。重组红细胞生成素（rEpo）是一种有效的神经保护剂，可改善新生儿和成年动物脑损伤后的短期和长期神经系统预后。低温治疗是围产期窒息的另一种有希望的治疗方法，可以改善轻度和中度缺氧缺血性脑病（HIE）婴儿的预后，但不能改善严重的HIE。不幸的是，无论是rEpo还是低温单独都不能提供完全的神经保护。我们的目标是开发一种安全有效的围产期窒息治疗方法，减少随后的神经损伤，从而帮助受影响的儿童充分发挥其潜力，过上健康和富有成效的生活。我们假设，在短尾猕猴（Macaca nemestrina）中，rEpo和低温治疗都会减少围产期窒息的神经发育和结构后果，但rEpo和低温联合治疗将提供更大的益处。我们已经建立了围产期窒息灵长类动物模型，这是理想的联合神经保护治疗策略的临床前评估的条件下，非常类似于人类新生儿紧急情况。我们将利用该模型来检验以下具体目标：目的1)确定哪种治疗策略在减少近期nemestrina M.围产期窒息的神经发育后遗症方面最有效：单独rEpo，单独低温治疗，或rEpo +低温治疗（与对照对照）；目的2)确定哪种治疗策略在减少近期nemestrina m的围产期大脑窒息的结构性后果方面最有效：单独rEpo，单独低温治疗，或rEpo加低温治疗（与对照对照）；目的3)确定高剂量rEpo治疗、低温和rEpo加头部冷却对近期围产期窒息的nemestrina的安全性。评估将包括脑电图、脑功能监测、MRI/MRS、神经行为评估、生化和免疫组织化学研究。将测试几种神经保护机制：1)低体温会保护神经元免于死亡，导致在9个月大时出现更多的神经元；2)低体温会刺激神经发生，导致在9个月大时出现更多的新神经元（BrdU标记）；3)低体温和低体温会减少炎症；4)低体温会增加铁的利用，从而减少氧化损伤。这项工作将产生重要的数据直接临床应用围产期窒息，并可能在其他机制的脑损伤的婴儿和儿童。

DESCRIPTION (provided by applicant): 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.