1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.
2 The Pathobiology Graduate Training Program, Johns Hopkins University, Baltimore, MD, USA.
J Cereb Blood Flow Metab. 2018 Dec;38(12):2092-2111. doi: 10.1177/0271678X18797328. Epub 2018 Aug 28.
Perinatal hypoxia-ischemia resulting in death or lifelong disabilities remains a major clinical disorder. Neonatal models of hypoxia-ischemia in rodents have enhanced our understanding of cellular mechanisms of neural injury in developing brain, but have limitations in simulating the range, accuracy, and physiology of clinical hypoxia-ischemia and the relevant systems neuropathology that contribute to the human brain injury pattern. Large animal models of perinatal hypoxia-ischemia, such as partial or complete asphyxia at the time of delivery of fetal monkeys, umbilical cord occlusion and cerebral hypoperfusion at different stages of gestation in fetal sheep, and severe hypoxia and hypoperfusion in newborn piglets, have largely overcome these limitations. In monkey, complete asphyxia produces preferential injury to cerebellum and primary sensory nuclei in brainstem and thalamus, whereas partial asphyxia produces preferential injury to somatosensory and motor cortex, basal ganglia, and thalamus. Mid-gestational fetal sheep provide a valuable model for studying vulnerability of progenitor oligodendrocytes. Hypoxia followed by asphyxia in newborn piglets replicates the systems injury seen in term newborns. Efficacy of post-insult hypothermia in animal models led to the success of clinical trials in term human neonates. Large animal models are now being used to explore adjunct therapy to augment hypothermic neuroprotection.
围产期缺氧缺血导致死亡或终身残疾仍然是一种主要的临床疾病。啮齿动物的新生儿缺氧缺血模型增强了我们对发育中大脑神经损伤的细胞机制的理解，但在模拟临床缺氧缺血的范围、准确性和生理学以及导致人类脑损伤模式的相关系统神经病理学方面存在局限性。围产期缺氧缺血的大动物模型，如分娩时胎儿猴子的部分或完全窒息、胎儿羊在不同妊娠阶段的脐带结扎和脑灌注不足，以及新生仔猪的严重缺氧和低灌注，在很大程度上克服了这些局限性。在猴子中，完全窒息导致小脑和脑干及丘脑的初级感觉核优先损伤，而部分窒息导致躯体感觉和运动皮层、基底节和丘脑优先损伤。中孕期胎儿羊为研究祖细胞少突胶质细胞的易感性提供了有价值的模型。新生仔猪的缺氧后继发窒息复制了足月新生儿的系统损伤。动物模型中损伤后低温治疗的疗效导致了足月人类新生儿临床试验的成功。大动物模型现在正被用于探索辅助治疗以增强低温神经保护作用。
