Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition
Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition
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DOI：
10.1016/j.nbd.2005.10.011
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发表时间：
2006-04-01
影响因子：
6.1
通讯作者：
Meaney, DF
中科院分区：
文献类型：
--
作者：
DeRidder, MN;Simon, MJ;Meaney, DF
海马细胞凋亡或坏死是脑外伤后认知功能障碍的主要原因。在这项研究中，我们研究了创伤性机械损伤是否会产生区域激活的钙蛋白酶和caspase-3在体外海马和研究如何机械诱导激活NR 2A和NR 2B含有N-甲基-D-天冬氨酸受体（NMDARs）影响这些蛋白酶的激活后，机械损伤。经过75%的拉伸，激活的caspase-3和钙蛋白酶介导的血影蛋白分解产物的显着水平仅在齿状回内的细胞中是明显的，并且在单个细胞内鉴定出很少的标记物共定位。在100%拉伸后，仅观察到钙蛋白酶激活，在拉伸后24小时定位于CA 3亚区。在中度损伤水平下，通过在牵张之前阻断含有NR 2B的NMDAR或通过在牵张损伤之前阻断所有NMDAR来减弱半胱天冬酶-3和钙蛋白酶活化。用NR 2A选择性NMDAR拮抗剂治疗对中度损伤后激活的caspase-3或Ab 38免疫反应性影响不大，但导致严重机械拉伸后齿状回中出现激活的caspase-3。总之，这些研究表明，损伤诱导的含有NR 2A的NMDAR的激活起促存活信号的作用，而含有NR 2B的NMDAR的激活是海马机械损伤后的竞争性抗存活信号。(c)2005年爱思唯尔文件。All rights reserved.
Apoptotic or necrotic cell death in the hippocampus is a major factor underlying the cognitive impairments following traumatic brain injury. In this study, we examined if traumatic mechanical injury would produce regional activation of calpain and caspase-3 in the in vitro hippocampus and studied how the mechanically induced activation of NR2A and NR2B containing N-methyl-D-aspartate receptors (NMDARs) affects the activation of these proteases following mechanical injury. Following a 75% stretch, significant levels of activated caspase-3 and calpain-mediated spectrin breakdown products were evident only in cells within the dentate gyrus, and little co-localization of the markers was identified within individual cells. After 100% stretch, only calpain activation was observed, localized to the CA3 subregion 24 It after stretch. At moderate injury, levels, both caspase-3 and calpain activation was attenuated by blocking NR2B containing NMDARs prior to stretch or by blocking all NMDARs prior to stretch injury. Treatment with an NR2A selective NMDAR antagonist had little effect on either activated caspase-3 or Ab38 immunoreactivity following moderate injury but resulted in the appearance of activated caspase-3 in the dentate gyrus following severe mechanical stretch. Together, these studies suggest that the injury induced activation of NR2A containing NMDARs functions as a pro-survival signal, while the activation of NR2B containing NMDARs is a competing, anti-survival, signal following mechanical injury to the hippocampus. (c) 2005 Elsevier file. All rights reserved.