Research on brain hypothermia for neonatal hypoxic-ischemic brain damage

本研究的目的是确定脑低温对新生儿缺氧缺血性脑损伤的疗效。全身低温和半胱氨酸天冬氨酸氨基转移酶抑制剂对发育中大鼠海马神经元的保护作用在结扎左侧颈动脉并暴露于8%O2 1h的P7大鼠HI模型上，发现全身低温(30℃)和泛型半胱氨酸天冬氨酸氨基转移酶抑制剂(BAF)可抑制Caspase-3的激活，减轻同侧海马神经细胞的丢失。结论：1.全身低温可抑制Hi诱导的caspase-3活性升高，约为常温组的一半，与BAF联合应用后7d海马神经细胞损失率明显降低至5%，而常温组仅为37%。选择性脑低温减少发育期大鼠缺氧缺血再灌流过程中羟基自由基的产生。采用P7HI(90min)和再灌流模型，证明选择性脑低温(30~32℃)能显著降低Hi所致的羟基自由基升高。选择性低温可显著减少同侧海马区、纹状体和皮质的坏死和凋亡细胞数，提示脑低温可减少缺氧再灌注所致的caspase-3的激活和羟基自由基的产生，可能对发育中的脑细胞的坏死和凋亡具有保护作用。

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.