Optimizing Neuroprotection Following Perinatal Asphyxia

描述(申请人提供)：围产期窒息仍然是一个严重的问题，占全球新生儿死亡的23%。高达60%的幸存者患有终身神经发育障碍，包括智力低下、脑瘫、癫痫发作和学习障碍。目前有效的治疗策略有限。重组促红细胞生成素(Repo)是一种有效的神经保护剂，可改善新生和成年动物脑损伤后的短期和长期神经预后。低温是围产期窒息的另一种有前景的治疗方法，可以改善轻、中度缺氧缺血性脑病(HIE)婴儿的预后，但不能改善重度HIE。不幸的是，仅靠回购或低温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潜力，过上健康和富有成效的生活。我们假设，回购和低温都将减少围产期窒息对近期短尾猴(Macaca Nemstrina)的神经发育和结构影响，但回购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的灵长类动物模型，该模型非常适合在非常类似于人类新生儿紧急情况的条件下对联合神经保护治疗策略进行临床前评估。我们将利用这个模型来测试以下特定目标：目的1)确定哪种治疗策略在减少围产期窒息的神经发育后遗症方面最有效：单独回购，单独低温，还是回购加低温(与赋形剂对照组相比)；目的2)确定哪种治疗策略在减少围产期窒息对近期新月形吸虫脑的结构性后果方面最有效：仅回购，单独降温，或回购加低温(与赋形剂对照组相比)；目的3)探讨大剂量回购、低温、回购加头部降温治疗围产期窒息新月形吸虫的安全性。评估将包括EEG、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)repo？低温将保护神经元免受死亡，导致9个月龄时出现更多神经元2)repo将刺激神经再生，导致9个月龄时出现更多新神经元(BrdU标记)，3)repo和低温将减少炎症，4)repo将增加铁的利用，从而减少氧化损伤。这项工作将产生重要的数据，直接应用于围产期窒息，并可能对婴儿和儿童脑损伤的其他机制进行研究。

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.