Davidson Joanne O, Gonzalez Fernando, Gressens Pierre, Gunn Alistair J
Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
Department of Pediatrics, University of California, San Francisco, CA, USA.
Semin Fetal Neonatal Med. 2021 Oct;26(5):101267. doi: 10.1016/j.siny.2021.101267. Epub 2021 Jul 8.
Therapeutic hypothermia is now well established to significantly improve survival without disability after neonatal encephalopathy (NE). To further improve outcomes, we need to better understand the mechanisms of brain injury. The central finding, which offers the potential for neuroprotective and neurorestorative interventions, is that brain damage after perinatal hypoxia-ischemia evolves slowly over time. Although brain cells may die during profound hypoxia-ischemia, even after surprisingly severe insults many cells show transient recovery of oxidative metabolism during a "latent" phase characterized by actively suppressed neural metabolism and activity. Critically, after moderate to severe hypoxia-ischemia, this transient recovery is followed after ~6 h by a phase of secondary deterioration, with delayed seizures, failure of mitochondrial function, cytotoxic edema, and cell death over ~72 h. This is followed by a tertiary phase of remodeling and recovery. This review discusses the mechanisms of injury that occur during the primary, latent, secondary and tertiary phases of injury and potential treatments that target one or more of these phases. By analogy with therapeutic hypothermia, treatment as early as possible in the latent phase is likely to have the greatest potential to prevent injury ("neuroprotection"). In the secondary phase of injury, anticonvulsants can attenuate seizures, but show limited neuroprotection. Encouragingly, there is now increasing preclinical evidence that late, neurorestorative interventions have potential to improve long-term outcomes.
治疗性低温现已被充分证实可显著提高新生儿脑病（NE）后无残疾生存的几率。为进一步改善治疗效果，我们需要更好地了解脑损伤的机制。一个关键发现为神经保护和神经修复干预提供了可能，即围产期缺氧缺血后脑损伤会随时间缓慢发展。尽管脑细胞可能在严重缺氧缺血期间死亡，但即使遭受了令人惊讶的严重损伤，许多细胞在以神经代谢和活动被积极抑制为特征的“潜伏期”仍表现出氧化代谢的短暂恢复。至关重要的是，在中度至重度缺氧缺血后，这种短暂恢复在约6小时后会进入继发性恶化阶段，在约72小时内出现延迟性癫痫发作、线粒体功能衰竭、细胞毒性水肿和细胞死亡。随后是重塑和恢复的第三阶段。本综述讨论了在损伤的初级、潜伏、继发和第三阶段发生的损伤机制以及针对这些阶段中一个或多个阶段的潜在治疗方法。与治疗性低温类似，在潜伏期尽早治疗可能最有潜力预防损伤（“神经保护”）。在损伤的继发阶段，抗惊厥药物可减轻癫痫发作，但神经保护作用有限。令人鼓舞的是，现在越来越多的临床前证据表明，后期的神经修复干预有改善长期预后的潜力。
