Decreased extracellular adenosine levels lead to loss of hypoxia-induced neuroprotection after repeated episodes of exposure to hypoxia.
Decreased extracellular adenosine levels lead to loss of hypoxia-induced neuroprotection after repeated episodes of exposure to hypoxia.
复制标题
反复缺氧后，细胞外腺苷水平降低会导致缺氧诱导的神经保护作用丧失。
DOI：
10.1371/journal.pone.0057065
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Cui M;Bai X;Li T;Chen F;Dong Q;Zhao Y;Liu X
短暂性脑缺血发作（TIA）后达到长期的神经保护状态可能会有效减少与复发性卒中相关的脑损伤和神经功能障碍。HPC是一种提前暴露于轻度缺氧减少随后TIA产生的每搏输出量的现象。然而，这种神经保护作用并不持久，3天后达到高峰。因此，在这项研究中，我们研究了在不同时间间隔多次缺氧暴露的使用，以诱导小鼠中风模型的长期保护。C57 BL/6小鼠进行不同的低氧预适应方案：单次HPC或5次相同的事件，间隔3天（E3 d HPC）或6天（E6 d HPC）。最后一次低氧暴露后3天，诱导暂时性大脑中动脉闭塞（MCAO）。采用定量PCR方法检测不同HPC方案对缺氧诱导因子（HIF）调控基因mRNA表达的影响。细胞外腺苷浓度的变化，已知发挥神经保护作用，也测量使用体内微透析和高压液相色谱法（HPLC）。E6 d HPC提供神经保护，而E3 d HPC不提供。HIF调节的靶基因表达在所有HPC方案后显著增加。然而，E3 d HPC显着降低细胞外腺苷和减少脑血流量在缺血区域的腺苷转运蛋白，平衡核苷转运蛋白1（ENT 1）的表达上调。ENT 1抑制剂丙戊茶碱增加了E3 d HPC的脑血流量并重新建立了神经保护作用。腺苷受体特异性拮抗剂研究表明，腺苷主要通过A1受体介导HPC的神经保护作用。我们的数据表明，HIF调控基因和细胞外腺苷的合作是必要的HPC诱导的神经保护。
Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs) is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC) or 6 days (E6d HPC). Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO) was induced. The effects of these HPC protocols on hypoxia-inducible factor (HIF) regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC). Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1). An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF-regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection.