Inhibition of Na+/H+ Exchanger Isoform 1 Is Neuroprotective in Neonatal Hypoxic Ischemic Brain Injury
Inhibition of Na+/H+ Exchanger Isoform 1 Is Neuroprotective in Neonatal Hypoxic Ischemic Brain Injury
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DOI：
10.1089/ars.2010.3468
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发表时间：
2011-05-01
影响因子：
6.6
通讯作者：
Sun, Dandan
中科院分区：
文献类型：
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作者：
Cengiz, Pelin;Kleman, Neil;Sun, Dandan
我们研究了Na+/H+交换体亚型1（NHE-1）在新生儿缺氧缺血（HI）中的作用。HI诱导单侧结扎左颈总动脉在出生后第9天（P9）小鼠，随后暴露于8%O-2的动物55分钟。前/后处理组接受了选择性和有效的NHE-1抑制剂HOE 642（0.5 mg/kg，腹腔注射）5分钟前HI，然后在24和48小时后HI。给药后组在HI后10 min、24 h和48 h接受HOE 642（0.5 mg/kg）。盐水注射液用作溶剂对照。HI后72 h，溶剂对照组大脑在同侧海马、纹状体和丘脑中表现出神经元变性，如Fluoro-Jade C阳性染色和微管相关蛋白2（MAP 2）表达丧失所示。NHE-1蛋白在胶质细胞酸性蛋白阳性反应星形胶质细胞中表达上调。在HOE 642处理的脑中，形态海马结构得到更好的保留，显示出更少的神经变性和更高水平的MAP 2表达。在HI后4周龄时，在溶剂对照组中检测到运动学习缺陷。抑制P9小鼠NHE-1不仅可以减轻HI急性期的神经退行性变，而且可以改善HI后8周龄时纹状体依赖性运动学习和空间学习。这些结果表明，NHE-1介导的离子稳态破坏有助于新生儿HI后纹状体和CA 1锥体神经元损伤。抗氧化剂。氧化还原信号。14，1803-1813.
We investigated the role of Na+/H+ exchanger isoform 1 (NHE-1) in neonatal hypoxia/ischemia (HI). HI was induced by unilateral ligation of the left common carotid artery in postnatal day 9 (P9) mice, and subsequent exposure of animals to 8% O-2 for 55 min. A pre/posttreatment group received a selective and potent NHE-1 inhibitor HOE 642 (0.5 mg/kg, intraperitoneally) 5 min before HI, then at 24 and 48 h after HI. A posttreatment group received HOE 642 (0.5 mg/kg) at 10 min, 24 h, and 48 h after HI. Saline injections were used as vehicle controls. The vehicle-control brains at 72 h after HI exhibited neuronal degeneration in the ipsilateral hippocampus, striatum, and thalamus, as identified with Fluoro-Jade C positive staining and loss of microtubule-associated protein 2 (MAP2) expression. NHE-1 protein was upregulated in glial fibrillary acidic protein-positive reactive astrocytes. In HOE 642-treated brains, the morphologic hippocampal structures were better preserved and displayed less neurodegeneration and a higher level of MAP2 expression. Motor-learning deficit was detected at 4 weeks of age after HI in the vehicle control group. Inhibition of NHE-1 in P9 mice not only reduced neurodegeneration during the acute stage of HI but also improved the striatum-dependent motor learning and spatial learning at 8 weeks of age after HI. These findings suggest that NHE-1-mediated disruption of ionic homeostasis contributes to striatal and CA1 pyramidal neuronal injury after neonatal HI. Antioxid. Redox Signal. 14, 1803-1813.