Intraischemic but not postischemic hypothermia prevents non-selective hippocampal downregulation of AMPA and NMDA receptor gene expression after global ischemia
Intraischemic but not postischemic hypothermia prevents non-selective hippocampal downregulation of AMPA and NMDA receptor gene expression after global ischemia
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DOI：
10.1016/s0169-328x(00)00252-7
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发表时间：
2001-01-31
期刊：
影响因子：
--
通讯作者：
Globus, MYT
中科院分区：
文献类型：
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作者：
Friedman, LK;Ginsberg, MD;Globus, MYT
低温可能通过N-甲基-D-天冬氨酸(N-甲基-D-天冬氨酸)或钙离子通透性AMPA(α--amino-3-hydroxy-5-methyl-4-isoxazole-propionic酸)受体阻止钙离子内流，从而对缺血诱导的组织学神经保护作用。采用原位杂交法检测大鼠短暂性全脑缺血10min后，在有或无脑内或缺血后30℃低温条件下，海马区GluR1(A)、GluR2(B)、GluR3(C)和NMDAR1(NR1)亚单位的表达。常温缺血1d，GluR1(A)、GluR2(B)和GluR3(C)受体mRNAs的表达在易损性CA1显著抑制。不那么脆弱的CA3a-c亚区也被大幅下调。CA1组NR1mRNA表达降低，但低于AMPA mRNAs。在CA1细胞显著丢失的常温缺血后7天，CA1的三种AMPA转录本几乎都不存在，但仍有一定比例(33.9+/-7.2%)的NR1mRNA表达。缺血后1d和7d，亚低温可完全阻断损伤和非选择性基因表达下调。相比之下，缺血后亚低温延缓了神经元的变性，但仅部分恢复了AMPA和NR1mRNAs的表达，仅在损伤后7d，而不是在损伤后1d。因此，常温全脑缺血后，海马AMPA受体mRNAs以相对相似的速度下降，而缺血内低温对细胞的保护作用不依赖于AMPA受体亚单位组成的改变。由于在缺血后抗性神经元内持续减少，AMPA受体介导的钙电流可能不会导致选择性易损性。(C)2001 Elsevier Science B.V.保留所有权利。
Hypothermia may afford histological neuroprotection induced by ischemia by preventing aberrant Ca2+ influx through NMDA (N-methyl-D-aspartic acid) or Ca2+-permeable AMPA (alpha -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors. Expression of hippocampal GluR1(A), GluR2(B), GluR3(C) and NMDAR1 (NR1) subunits was investigated by in situ hybridization at 1 and 7 days after 10-min transient global ischemia in the presence and absence of intraischemic or postischemic brain hypothermia (30 degreesC). At 1 day, normothermic ischemia markedly suppressed the expression of GluR1(A), GluR2(B), and GluR3(C) receptor mRNAs to a similar degree in the vulnerable CA1. Less vulnerable CA3a-c subregions were also acutely downregulated. NR1 mRNA expression was reduced in CA1 but to a lesser extent than AMPA mRNAs. At 7 days after normothermic ischemia, a time of marked CA1 cell loss, all three AMPA transcripts were nearly absent in CA1 while a percentage (33.9+/-7.2%) of NR1 mRNA remained. Intraischemic hypothermia fully blocked the damage and non-selective mRNA downregulations at 1 and 7 days. By contrast, postischemic hypothermia postponed neurodegeneration but only partially rescued the expression of AMPA and NR1 mRNAs at 7 days and not at 1 day after the insult. Therefore, hippocampal AMPA receptor mRNAs decline at a relatively similar rate after normothermic global ischemia and cellular neuroprotection by intraischemic hypothermia occurred independently of altered subunit composition of AMPA receptors. Since decreases persist within resistant neurons under the postischemic condition, AMPA receptor-mediated Ca2+ currents probably do not contribute to selective vulnerability. (C) 2001 Elsevier Science B.V. All rights reserved.