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Potential circadian effects on translational failure for neuroprotection

机译：潜在的昼夜昼夜对神经保护失效的影响

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Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans(1,2) may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger alpha-phenyl-butyl-tert-nitrone (alpha PBN), and the N-methyl-d-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. alpha PBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.Studies in rats and mice at different times of day suggest that the failure of neuroprotective strategies for stroke in translational studies might be related to the difference in circadian cycles between humans and rodents.
机译：在啮齿动物的中风模型中工作的神经保护症策略未能在临床试验中提供保护。在这里，我们表明夜间啮齿动物与昼夜人类（1,2）的相反的昼夜循环可能有助于这种翻译失败。我们测试了三种独立的神经保护方法 - 正常性高氧，自由基清除剂α-苯基 - 叔丁酮（αPBN），以及N-甲基-D-天冬氨酸（NMDA）拮抗剂MK801-在小鼠和大鼠模型中焦点脑缺血。所有三种治疗在白时间（无活性相）啮齿动物的中风模型中，但不在夜间（活性期）啮齿动物中风模型中，这与大多数笔触发生的相位（活性，日间）相匹配临床试验。激光斑点成像显示，脑缺血的半影在活性相位模型中较窄，而不是无效相位模型。较小的PENUMBRA与较低的末端脱氧核苷酸转移酶DUTP碎片末端标记（TUNEL） - 阳性染色细胞的密度相关，并减少12至72小时的梗塞生长。当我们诱导原发性小鼠神经元的昼夜循环时，缺乏氧气和葡萄糖的谷氨酸和反应性氧物质的释放引发，以及凋亡和坏死介质的活化较低，在“活性相”中的激活 - 阶段'啮齿动物神经元。 Alpha PBN和MK801仅在“无活性阶段”神经元中降低了神经元死亡。这些研究结果表明，昼夜节律对神经保护的影响必须考虑中风和中枢神经系统疾病的翻译研究。不同时间的大鼠和小鼠的研究表明，翻译研究中卒中的神经保护策略的失败可能是相关的对人与啮齿动物之间的昼夜循环差异。

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  • 来源
    《Nature》 |2020年第7812期|395-398|共4页
  • 作者

    Esposito Elga; Li Wenlu; T. Mandeville Emiri; Park Ji-Hyun; Sencan Ikbal; Guo Shuzhen; Shi Jingfei; Lan Jing; Lee Janice; Hayakawa Kazuhide; Sakadzic Sava; Ji Xunming; Lo Eng H.;

  • 作者单位

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA|Seoul Natl Univ Coll Pharm Seoul South Korea;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Athinoula Martinos Ctr Biomed Imaging Boston MA 02115 USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA|Capital Med Univ XuanWu Hosp Cerebrovasc Res Inst Beijing Peoples R China;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA|Capital Med Univ XuanWu Hosp Cerebrovasc Res Inst Beijing Peoples R China;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Athinoula Martinos Ctr Biomed Imaging Boston MA 02115 USA;

    Capital Med Univ XuanWu Hosp Cerebrovasc Res Inst Beijing Peoples R China;

    Harvard Med Sch Massachusetts Gen Hosp Dept Radiol Neuroprotect Res Labs Boston MA 02115 USA|Harvard Med Sch Massachusetts Gen Hosp Dept Neurol Neuroprotect Res Labs Boston MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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