Research on brain hypothermia for neonatal hypoxic-ischemic brain damage

本研究的目的是确定脑低温治疗新生儿缺氧缺血性脑损伤的疗效。全身低温和caspase抑制剂对发育大鼠海马神经元抗HI损伤的保护作用。采用左颈动脉结扎诱导的P7大鼠HI模型，在8% O_2环境下暴露1小时，我们发现30℃的全身低温和泛caspase抑制剂BAF可以抑制caspase-3的激活，减轻同侧海马神经元细胞的损失。全身低温使高体温组的caspase-3活性升高幅度降至正常体温组的一半左右，联合BAF后caspase-3活性不再升高。全身低温联合BAF组海马神经元细胞的损失在HI后第7天显著降低至5%，而常温组为37%。选择性脑低温降低发育大鼠HI和再灌注过程中羟基自由基的产生。通过P7 HI （90min）和再灌注模型，我们发现选择性脑低温（30-32℃）可以显著降低HI诱导的羟基自由基的增加。选择性低温显著减少同侧海马、纹状体和皮质中坏死细胞和凋亡细胞的数量。这些结果表明，脑低温降低了HI损伤和再灌注诱导的caspase-3的激活和羟基自由基的产生，这可能对发育中的大脑中坏死和凋亡的神经元细胞损伤具有保护作用。

The aim of this study is to determine the efficacy of brain hypothermia against neonatal hypoxic-ischemic (HI) brain damage.1. Systemic hypothermia and caspase inhibitor protect hippocampal neuron against HI insult in developing rat. Using P7 rat HI model induced by ligation of left carotid artery and exposure to 8% O_2 for 1h, we demonstrated that systemic hypothermia (30℃) and pan-caspase inhibitor, BAF, could inhibit activation of caspase-3 and lessen neuronal cell loss in ipsilateral hippocampus. Systemic hypothermia inhibited the Hi-induced increase of caspase-3 activity to about half of normothrmia group, and combination with BAF resulted in no increase of caspase-3 activity anymore.The loss of hippocampal neuronal cells at 7d after HI significantly reduced to 5% by combination of systemic hypothermia and BAF in contrast to 37% of normothermia group.2. Selective brain hypothermia reduces hydroxyl radical production during HI and reperfusion in developing rat. Using P7 HI (90min) and reperfusion model, we demonstrated that selective brain hypothermia (30-32℃) could reduce the Hi-induced increase in hydroxyl radical significantly. Selective hypothermia remarkably reduced the number of both necrotic and apoptotic cells in ipsilateral hippocampus, striatum and cortex.These results indicate that brain hypothermia reduces the activation of caspase-3 and production of hydroxyl radical induced by HI insult and reperfusion, which may have protective effects against necrotic and apoptotic neuronal cell damage in the developing brain.