Differential effects of hypothermia on neurovascular unit determine protective or toxic results: Toward optimized therapeutic hypothermia
Differential effects of hypothermia on neurovascular unit determine protective or toxic results: Toward optimized therapeutic hypothermia
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DOI：
10.1177/0271678x18814614
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发表时间：
2019-09-01
影响因子：
6.3
通讯作者：
Rajput, Padmesh S.
中科院分区：
文献类型：
--
作者：
Lyden, Patrick D.;Lamb, Jessica;Rajput, Padmesh S.
治疗性低温（TH）有益于心脏骤停和新生儿缺氧缺血性损伤的幸存者，并可能有益于中风患者。然而，大型TH临床试验显示了混合的结果。鉴于大量临床前文献支持TH，我们探索了临床试验变异性的可能机制。使用标准的啮齿动物中风模型（每组n = 20），我们发现再灌注TH前或后2小时的梗死比4小时的梗死小。为了探索这种差异的机制，我们使用了原代细胞培养的啮齿动物神经元，星形胶质细胞，或内皮细胞进行氧-葡萄糖剥夺（OGD）。然后，在不同的延迟时间之后，将细胞随机分配到33度、35度或37度，持续不同的持续时间。33度和35度TH均有效地保存了所有细胞类型，尽管33度上级。较长的冷却持续时间克服了冷却开始的中度延迟。与此相反，TH干扰星形胶质细胞旁分泌保护神经元的温度依赖性方式。这些研究结果表明，较长的TH是需要克服延迟TH发作，但较短的TH持续时间可能是上级更长，可能是由于抑制星形胶质细胞旁分泌支持的神经元损伤。我们提出了一个优化TH脑损伤后刺激心脏骤停和中风的进一步研究的计划。
Therapeutic hypothermia (TH) benefits survivors of cardiac arrest and neonatal hypoxic-ischemic injury and may benefit stroke patients. Large TH clinical trials, however, have shown mixed results. Given the substantial pre-clinical literature supporting TH, we explored possible mechanisms for clinical trial variability. Using a standard rodent stroke model (n = 20 per group), we found smaller infarctions after 2 h pre- or post-reperfusion TH compared to 4 h. To explore the mechanism of this discrepancy, we used primary cell cultures of rodent neurons, astrocytes, or endothelial cells subjected to oxygen-glucose deprivation (OGD). Then, cells were randomly assigned to 33 degrees, 35 degrees or 37 degrees for varying durations after varying delay times. Both 33 and 35 degrees TH effectively preserved all cell types, although 33 degrees was superior. Longer cooling durations overcame moderate delays to cooling initiation. In contrast, TH interfered with astrocyte paracrine protection of neurons in a temperature-dependent manner. These findings suggest that longer TH is needed to overcome delays to TH onset, but shorter TH durations may be superior to longer, perhaps due to suppression of astrocytic paracrine support of neurons during injury. We propose a scheme for optimizing TH after cerebral injury to stimulate further studies of cardiac arrest and stroke.