Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia
Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia
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DOI：
10.1111/jpi.12744
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发表时间：
2021-06-20
影响因子：
10.3
通讯作者：
Miller, Suzanne L.
中科院分区：
文献类型：
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作者：
Aridas, James DS.;Yawno, Tamara;Miller, Suzanne L.
治疗性低温（TH）是高资源分娩环境中新生儿脑病婴儿的标准护理。TH部分有效，需要辅助治疗。在这里，我们研究了抗氧化剂褪黑激素（MLT）是否提供了附加的好处与TH相比，TH单独或MLT单独，以改善新生羔羊急性脑病的恢复。在剖腹产分娩前，我们通过脐带阻塞诱导胎羊窒息，直到平均动脉血压从假手术对照组的55 +/- 3 mm Hg降至18-20 mm Hg（10.1 +/- 1.5分钟）。将羔羊交付并随机分配至对照组、对照组+ MLT（60 mg iv，30分钟至24小时）、窒息组、窒息+ TH（全身冷却至35.1 +/- 0.8 ℃，假手术对照组为38.3 +/- 0.17 ℃，4-28小时）、窒息+ MLT和窒息+ TH + MLT。在72小时时，进行磁共振波谱（MRS），然后收集大脑进行神经病理学评估。在MRS上，窒息诱导了脑代谢异常，乳酸：NAA增加（P = .003），NAA：胆碱减少（P = .005），诱导了灰质和白色脑区的凋亡和坏死细胞死亡（P < .05），并增加了神经炎症和氧化应激（P < .05）。与单独窒息相比，TH和MLT与氧化应激、炎症和细胞死亡的区域特异性减少独立相关。TH和MLT之间存在相互作用，窒息+ TH + MLT后NAA：胆碱比率与假手术对照组相比无显著差异，但神经病理学的总体降低幅度大于单独治疗。这项研究表明，在新生羔羊，联合TH + MLT新生儿脑病提供显着更大的神经保护比单独。这些结果将指导新生儿脑病进一步试验的发展。
Therapeutic hypothermia (TH) is standard care in high-resource birth settings for infants with neonatal encephalopathy. TH is partially effective and adjuvant therapies are needed. Here, we examined whether the antioxidant melatonin (MLT) provides additive benefit with TH, compared to TH alone or MLT alone, to improve recovery from acute encephalopathy in newborn lambs. Immediately before cesarean section delivery, we induced asphyxia in fetal sheep via umbilical cord occlusion until mean arterial blood pressure fell from 55 +/- 3 mm Hg in sham controls to 18-20 mm Hg (10.1 +/- 1.5 minutes). Lambs were delivered and randomized to control, control + MLT (60 mg iv, from 30 minutes to 24 hours), asphyxia, asphyxia + TH (whole-body cooling to 35.1 +/- 0.8 degrees C vs. 38.3 +/- 0.17 degrees C in sham controls, from 4-28 hours), asphyxia + MLT, and asphyxia + TH + MLT. At 72 hours, magnetic resonance spectroscopy (MRS) was undertaken, and then brains were collected for neuropathology assessment. Asphyxia induced abnormal brain metabolism on MRS with increased Lactate:NAA (P = .003) and reduced NAA:Choline (P = .005), induced apoptotic and necrotic cell death across gray and white matter brain regions (P < .05), and increased neuroinflammation and oxidative stress (P < .05). TH and MLT were independently associated with region-specific reductions in oxidative stress, inflammation, and cell death, compared to asphyxia alone. There was an interaction between TH and MLT such that the NAA:Choline ratio was not significantly different after asphyxia + TH + MLT compared to sham controls but had a greater overall reduction in neuropathology than either treatment alone. This study demonstrates that, in newborn lambs, combined TH + MLT for neonatal encephalopathy provides significantly greater neuroprotection than either alone. These results will guide the development of further trials for neonatal encephalopathy.