Prosurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus
Prosurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus
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DOI：
10.1002/hipo.22372
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发表时间：
2015-03
期刊：
影响因子：
3.5
通讯作者：
Xi Zhang;Quanguang Zhang;J. Tu;Ying Zhu;Fang Yang;B. Liu;D. Brann;Ruimin Wang
中科院分区：
文献类型：
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作者：
Xi Zhang;Quanguang Zhang;J. Tu;Ying Zhu;Fang Yang;B. Liu;D. Brann;Ruimin Wang
缺血后处理（Post C），涉及在初始缺血事件后给予短暂缺血，已被证明对全脑缺血（GCI）具有强烈的神经保护作用，并改善认知结果。为了加强对潜在机制的理解，本研究检查了NMDA受体在成年雄性大鼠GCI后2天给予Post C（3分钟缺血）的有益作用中的作用。结果显示，Post C对GCI具有强烈的神经保护作用，并且这种作用可通过给予NMDA受体拮抗剂MK-801来阻断。进一步的研究表明，NR 2A-型NMDA受体介导了C后有益作用，因为NR 2A-偏好拮抗剂（NVP-A）的给药阻断了C后神经保护和认知增强，而NR 2B-偏好拮抗剂（Ro 25）的给药则没有效果。C后显著上调海马CA 1区NR 2A水平和NR 2A磷酸化。C后还增加了Ca 2+内流和Thr 286处CamKIIα的活化/磷酸化，这些作用是NR 2A介导的，因为它们被NVP‐A阻断。Post C也增加了ERK和CREB的磷酸化，两种下游CREB依赖性促生存因子，脑源性神经营养因子（BDNF）和Bcl 2，其作用被NR 2A拮抗剂NVP-A阻断。总的来说，目前的研究提供了证据，证明NR 2A激活和下游促生存信号是GCI后C诱导的神经保护和认知增强的关键介质。© 2014 Wiley Periodicals，Inc.
Ischemic postconditioning (Post C), which involves administration of a brief ischemia after the initial ischemic event, has been demonstrated to be strongly neuroprotective against global cerebral ischemia (GCI) and to improve cognitive outcome. To enhance understanding of the underlying mechanisms, the current study examined the role of NMDA receptors in mediating the beneficial effects of Post C (3 min ischemia) administered 2 days after GCI in adult male rats. The results revealed that Post C was strongly neuroprotective against GCI, and that this effect was blocked by administration of the NMDA receptor antagonist MK‐801. Further work revealed that the NR2A‐type NMDA receptors mediate the Post C beneficial effects as administration of a NR2A‐preferring antagonist (NVP‐A) blocked Post C neuroprotection and cognitive enhancement, while administration of a NR2B‐preferring antagonist (Ro25) was without effect. Post C significantly up‐regulated NR2A levels and phosphorylation of NR2A in the hippocampal CA1 region after Post C. Post C also increased Ca2+ influx and activation/phosphorylation of CamKIIα at Thr286, effects that were NR2A mediated as they were blocked by NVP‐A. Phosphorylation of ERK and CREB was also increased by Post C, as were two downstream CREB‐dependent prosurvival factors, brain derived neurotropic factor (BDNF) and Bcl2, effects that were blocked by the NR2A antagonist, NVP‐A. Taken as a whole, the current study provides evidence that NR2A‐activation and downstream prosurvival signaling is a critical mediator of Post C‐induced neuroprotection and cognitive enhancement following GCI. © 2014 Wiley Periodicals, Inc.