Activation of NR2A Receptors Induces Ischemic Tolerance through CREB Signaling
Activation of NR2A Receptors Induces Ischemic Tolerance through CREB Signaling
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DOI：
10.1038/jcbfm.2010.18
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发表时间：
2010-08
影响因子：
6.3
通讯作者：
Y. Terasaki;Tsutomu Sasaki;Y. Yagita;Shuhei Okazaki;Y. Sugiyama;N. Oyama;E. Omura-Matsuoka;S. Sakoda-S.
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文献类型：
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作者：
Y. Terasaki;Tsutomu Sasaki;Y. Yagita;Shuhei Okazaki;Y. Sugiyama;N. Oyama;E. Omura-Matsuoka;S. Sakoda-S.
预先暴露于非致死性缺血损伤可保护脑免受随后的有害缺血损伤，N-甲基-D-天冬氨酸（NMDA）受体是缺血后神经保护作用的高度研究靶点。最近，NMDA受体亚型与神经元的存活和死亡有关。我们专注于NR 2A和环腺苷酸反应元件（CRE）结合蛋白（CREB）信号的贡献，缺血耐受使用原代皮层神经元。采用氧糖剥夺（OGD）法建立大鼠缺血模型。缺血耐受通过在180分钟OGD之前24小时施加45分钟OGD来诱导。亚致死OGD也诱导对致死谷氨酸和过氧化氢的交叉耐受。亚致死OGD后，磷酸化CREB的表达和CRE转录活性显著增加。当CRE活性被CREB突变体CREB-S133 A抑制时，缺血耐受被消除。使用NVP-AAM 077抑制NR 2A减弱了预处理诱导的神经保护作用，并与CRE活性水平降低相关。使用荷包牡丹碱和4-氨基吡啶激活NR 2A诱导对致死性缺血的抗性，伴随着CRE活性水平升高，并且这种作用被NVP-AAM 077消除。脑源性神经营养因子（BDNF）转录活性升高后，观察亚致死OGD和荷包牡丹碱和4-氨基吡啶管理。含NR 2A的NMDA受体和CREB信号在诱导缺血耐受中具有重要作用。这可能为治疗缺血性卒中提供潜在的新的治疗策略。
Previous exposure to a nonlethal ischemic insult protects the brain against subsequent harmful ischemia.N-methyl-D-aspartate (NMDA) receptors are a highly studied target of neuroprotection after ischemia. Recently, NMDA receptor subtypes were implicated in neuronal survival and death. We focused on the contribution of NR2A and cyclic-AMP response element (CRE)-binding protein (CREB) signaling to ischemic tolerance using primary cortical neurons. Ischemiain vitrowas modeled by oxygen–glucose deprivation (OGD). Ischemic tolerance was induced by applying 45-mins OGD 24 h before 180-mins OGD. Sublethal OGD also induced cross-tolerance against lethal glutamate and hydrogen peroxide. After sublethal OGD, expression of phosphorylated CREB and CRE transcriptional activity were significantly increased. When CRE activity was inhibited by CREB-S133A, a mutant CREB, ischemic tolerance was abolished. Inhibiting NR2A using NVP-AAM077 attenuated preconditioning-induced neuroprotection and correlated with decreased CRE activity levels. Activating NR2A using bicuculline and 4-aminopiridine induced resistance to lethal ischemia accompanied by elevated CRE activity levels, and this effect was abolished by NVP-AAM077. Elevated brain-derived neurotrophic factor (BDNF) transcriptional activities were observed after sublethal OGD and administration of bicuculline and 4-aminopiridine. NR2A-containing NMDA receptors and CREB signaling have important functions in the induction of ischemic tolerance. This may provide potential novel therapeutic strategies to treat ischemic stroke.