Sabir Hemmen, Walløe Lars, Dingley John, Smit Elisa, Liu Xun, Thoresen Marianne
Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
PLoS One. 2014 Oct 6;9(10):e109845. doi: 10.1371/journal.pone.0109845. eCollection 2014.
Breathing the inert gas Xenon (Xe) enhances hypothermic (HT) neuroprotection after hypoxia-ischemia (HI) in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added) or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7) rats, showed that the combination of mild HT (35°C) and low Xe concentration (20%), both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.
DESIGN/METHODS: After the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT) NT37°C, HT35°C, HT32°C) or Xe concentrations (0%, 20% or 50%) starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101) of P7 pups were exposed to either HT35°C+Xe0%, NT+Xe20% or a combination of HT35°C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side) brain tissue area loss after seven day survival.
Immediate HT32°C (p = 0.042), but not HT35°C significantly reduced brain injury compared to NT37°C. As previously shown, adding immediate Xe50% to HT32°C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37°C significantly reduced brain injury (p>0.050). In addition, neither 4 h-delayed HT35°C alone, nor HT35°C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.
Combining two treatments that individually were ineffective (delayed HT35°C and delayed Xe20%) did not exert neuroprotection when combined, and therefore did not show a synergistic treatment effect.
在新生小动物和大动物模型中，吸入惰性气体氙（Xe）可增强缺氧缺血（HI）后的低温（HT）神经保护作用。这种增强作用的潜在机制尚未完全阐明，但Xe和HT的联合作用可能是协同的（大于两者作用之和），也可能只是相加的。之前发表的一项研究，对7日龄（P7）大鼠进行单侧颈动脉结扎后再进行缺氧处理，结果显示，轻度低温（35°C）和低浓度Xe（20%）单独使用时均无神经保护作用，但二者联合且在中度HI损伤后延迟4小时开始应用时具有协同作用且具有神经保护作用。为了检验其他实验室能否证实这一发现，我们重复了该研究的关键部分。
设计/方法：120只幼崽在HI损伤后接受不同的损伤后处理：三种温度（正常体温（NT）37°C、低温35°C、低温32°C）或Xe浓度（0%、20%或50%），处理要么立即开始，要么延迟4小时开始。为了评估Xe-HT的协同效力，第二组（n = 101）P7幼崽在损伤后延迟4小时开始接受35°C低温+0% Xe、正常体温+20% Xe或35°C低温+20% Xe的联合处理。在存活7天后，使用相对半球（结扎侧/未结扎侧）脑组织面积损失分析脑损伤情况。
与37°C正常体温相比，立即进行32°C低温（p = 0.042）可显著降低脑损伤，但35°C低温无此作用。如之前所示，在32°C低温基础上立即添加50% Xe可增强保护作用。延迟4小时的20% Xe以及37°C时的50% Xe均未显著降低脑损伤（p>0.050）。此外，单独延迟4小时的35°C低温以及35°C低温+20% Xe均未降低脑损伤。在该实验模型中，我们未发现联合处理具有协同作用。
两种单独无效的处理（延迟35°C低温和延迟20% Xe）联合应用时未发挥神经保护作用，因此未显示出协同治疗效果。
