The effect of hypothermia therapy on cortical laminar disruption following ischemic injury in neonatal mice.
The effect of hypothermia therapy on cortical laminar disruption following ischemic injury in neonatal mice.
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DOI：
10.1371/journal.pone.0068877
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Suzuki M
中科院分区：
文献类型：
--
作者：
Kida H;Nomura S;Shinoyama M;Ideguchi M;Owada Y;Suzuki M
低温已被提出作为一种治疗方法，以减少脑缺血引起的神经元损伤。在发育中的大脑中，缺氧缺血性损伤可引起脑瘫（CP）。然而，低温是否会影响CP的发展尚不清楚。本研究的目的是研究低温是否会对脑缺血后未成熟3天龄（P3）小鼠的大脑产生保护作用。P3小鼠右颈总动脉结扎后缺氧（6% O2, 37°C） 30min，诱导脑缺血。缺氧缺血后，立即将小鼠暴露于低温（32°C）或常温（37°C）中24小时。在4周龄时，通过行为测试测试小鼠的运动发育。小鼠在P4、P7和5周时处死，观察脑形态。免疫组化检测皮层层状结构（Cux1/Ctip2）；计算神经元数量；测定髓鞘碱性蛋白（MBP）的表达。在行为测试中，低温治疗与神经学结果的改善有关。在正常体温组，组织学分析表明，与对侧皮质相比，神经元数量减少，深部皮质层厚度减少，缺血皮质中MBP表达明显减少。在低温组中，与对侧皮质相比，深部皮质层厚度和缺血皮质的MBP表达没有减少。在低温治疗24小时后，正常体温治疗可以防止主要发生在缺血皮质深层的神经元细胞死亡。本研究结果可为低温治疗早产儿缺氧缺血所致CP的临床前试验提供依据。
Hypothermia has been proposed as a treatment for reducing neuronal damage in the brain induced by hypoxic ischemia. In the developing brain, hypoxic ischemia-induced injury may give rise to cerebral palsy (CP). However, it is unknown whether hypothermia might affect the development of CP. The purpose of this study was to investigate whether hypothermia would have a protective effect on the brains of immature, 3-day old (P3) mice after a challenge of cerebral ischemia. Cerebral ischemia was induced in P3 mice with a right common carotid artery ligation followed by hypoxia (6% O2, 37°C) for 30 min. Immediately after hypoxic ischemia, mice were exposed to hypothermia (32°C) or normothermia (37°C) for 24 h. At 4 weeks of age, mouse motor development was tested in a behavioral test. Mice were sacrificed at P4, P7, and 5 weeks to examine brain morphology. The laminar structure of the cortex was examined with immunohistochemistry (Cux1/Ctip2); the number of neurons was counted; and the expression of myelin basic protein (MBP) was determined. The hypothermia treatment was associated with improved neurological outcomes in the behavioral test. In the normothermia group, histological analyses indicated reduced numbers of neurons, reduced cortical laminar thickness in the deep, ischemic cortical layers, and significant reduction in MBP expression in the ischemic cortex compared to the contralateral cortex. In the hypothermia group, no reductions were noted in deep cortical layer thickness and in MBP expression in the ischemic cortex compared to the contralateral cortex. At 24 h after the hypothermia treatment prevented the neuronal cell death that had predominantly occurred in the ischemic cortical deep layers with normothermia treatment. Our findings may provide a preclinical basis for testing hypothermal therapies in patients with CP induced by hypoxic ischemia in the preterm period.
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