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延迟亚低温对缺血再灌注脑损伤后神经功能恢复和神经发生的影响

The Effects of Delayed Hypothermia on Functional Recovery and Neurogenesls after Ischemia-Reperfusion Brain Injury in Rat

【作者】 陈丽娟

【导师】 江克文;

【作者基本信息】 浙江大学 , 儿科学, 2016, 硕士

【摘要】 研究背景:对于缺血脑损伤,亚低温治疗是一种强大的神经保护策略。但病人往往是发病后才运送到医疗单位,延误了“最佳”低温治疗时机。这种延迟亚低温是否能促进神经功能恢复及其机制需要进一步阐明。神经发生(neurogenesis)是一种可能的低温保护机制。脑缺血后侧脑室室管膜下区(SVZ)和海马齿状回(DG)区细胞增殖增加;神经祖细胞迁移途径发生了改变,大量新增殖的细胞迁移至缺血损伤边缘;一小部分细胞能存活并分化为成熟的神经元或星形胶质细胞。缺血后亚低温能抑制氨基酸和单胺神经递质的过度释放、及炎症反应,但是否调节缺血后神经前体细胞的增殖和迁移还知之甚少。本课题首先探讨缺血后延迟亚低温对脑梗死面积和神经功能恢复的影响;其次研究检测脑缺血后延迟亚低温对细胞增殖和分化的影响。方法:制备局灶性脑缺血再灌注模型,缺血再灌注后15mmin降低中心温度到30℃维持3h来诱导延迟亚低温。应用行为学测试、溴脱氧尿苷(BrdU)标记、激光共聚焦显微镜细胞谱分析等方法来探讨延迟亚低温治疗对神经功能恢复和神经发生的影响。结果:延迟亚低温不能降低缺血梗死面积,但能促进神经功能恢复。同常温模型组相比,延迟亚低温能显著提高脑缺血后3h(缺血后立即给予BrdU标记一次)缺血侧SVZ区的新生细胞数(P<0.05)。延迟亚低温能显著提高缺血后7和14d(缺血后给予BrdU连续7d标记)缺血侧SVZ区的新生细胞积聚数(P<0.05);延迟亚低温能显著提高缺血后7d缺血侧DG区的新生细胞积聚数(P<0.05),却显著降低14d缺血侧DG区的新生细胞积聚数(P<0.05);对缺血半梗死区新生细胞聚集无明显影响。另外,延迟亚低温能提高缺血后一些时间点新生细胞与一些神经细胞标记物共定位的比例,包括DCX(未成熟神经元标记物)、Nestin(未成熟神经元或胶质细胞标志物)、GFAP (成熟星形胶质细胞标记物)、NG2(少突胶质细胞标记物)和NeuN(成熟神经元标记物)。结论:(1)延迟亚低温可促进神经功能恢复。(2)延迟亚低温可通过促进缺血后细胞增殖和新生细胞积聚、改变新生细胞的最终命运来减轻缺血性损伤、促进脑损伤的修复。

【Abstract】 Background and Purpose:In contrast to intra-ischemic mild or moderate hypothermia, relatively little is known about the protective mechanisms of delayed post-ischemic hypothermia against stroke. This study investigates whether a delayed hypothermia, which does not reduce infarct size, improves neurological function and stroke-induced neurogenesis.Methods:Delayed hypothermia was induced by reducing the core temperature of rats to 30℃ at 15 minutes after 1-hour transient focal ischemia and maintained for 3 hours. We used behavioral tests, bromodeoxyuridine (BrdU) labeling, and cell lineage analysis with confocal microscopy to determine functional recovery and neurogenesis.Results:Delayed hypothermia did not reduce infarction but improved functional outcomes. In contrast to normothermia, delayed hypothermia increased BrdU+ cell numbers measured at 3 hours in the ipsilateral subventricular zone (SVZ) with a single pulse of BrdU. For rats receiving BrdU labeling 7 consecutive days after stroke, the accumulated BrdU+ cell numbers increased at 7 and 14 days in the ipsilateral SVZ of the hypothermic but not the normothermic brain; however, cell numbers increased at 7 days but decreased at 14 days in the ipsilateral dentate gyrus, and did not change in the peri-infarct region. Additionally, hypothermia increased the fraction of BrdU+ cells co-labeled with doublecortin, Nestin, NeuN, glial fibrillary acidic protein, or NG2 at some post-ischemic time points.Conclusions:Delayed hypothermia may prevent ischemic damage and improve functional outcomes in part by enhancing cell proliferation or altering the fate of newborn cells following stroke.

  • 【网络出版投稿人】 浙江大学
  • 【网络出版年期】2017年 02期
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