Potential circadian effects on translational failure for neuroprotection.
Potential circadian effects on translational failure for neuroprotection.
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作者：
神经保护剂在啮齿动物模型中起作用，但在临床中风试验中失败。在这里，我们询问夜间活动的啮齿动物与白天活动的人类的相反昼夜周期是否可能导致这种翻译失败。我们在小鼠和大鼠局灶性脑缺血模型中测试了3种独立的神经保护方法-正压高氧，自由基清除剂αPBN和n -甲基-d-天冬氨酸（NMDA）拮抗剂MK801。在白天（非活动期）啮齿类动物模型中，所有3种治疗方法均减少了梗死。所有三种治疗方法在夜间（活动期）啮齿动物模型中都失败了，这些模型与招募进入临床试验的白天清醒的患者相匹配。激光散斑成像显示，与非活动相小鼠相比，活动相小鼠的半暗带变窄。较小的半暗带与末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性的死亡细胞密度较低有关，并且在12至72小时内减少了梗死生长。在小鼠原代神经元中诱导类似昼夜节律的周期后，氧-葡萄糖剥夺触发了“活跃期”与“不活跃期”啮齿动物神经元中较小的谷氨酸和活性氧（ROS）的释放，以及较低的凋亡和坏死介质的激活。α - pbn和MK801仅在“非活跃期”神经元中减少神经元死亡。这些发现表明，在卒中和中枢神经系统（CNS）疾病的转译研究中，必须考虑昼夜节律对神经保护的影响。
Neuroprotectants have worked in rodent models but failed in clinical stroke trials. Here, we asked whether opposite circadian cycles in nocturnal rodents versus diurnal humans may contribute to this failure in translation. We tested 3 independent neuroprotective approaches in mouse and rat models of focal cerebral ischemia – normobaric hyperoxia, the free radical scavenger αPBN, and the N-Methyl-d-aspartic acid (NMDA) antagonist MK801. All 3 treatments reduced infarction in day-time (inactive-phase) rodent models. All 3 treatments failed in night-time (active-phase) rodent models that match awake day-time patients who are recruited into clinical trials. Laser-speckle imaging showed that the penumbra was narrower in active-phase compared to inactive-phase mice. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 hrs. After inducing circadian-like cycles in primary mouse neurons, oxygen-glucose deprivation triggered a smaller release of glutamate and reactive oxygen species (ROS) as well as a lower activation of apoptotic and necroptotic mediators in “active-phase” versus “inactive-phase” rodent neurons. αPBN 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 (CNS) disease.
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影响因子：
5.1
作者：
Beker, Mustafa Caglar;Caglayan, Berrak;Kilic, Ertugrul
通讯作者：
Kilic, Ertugrul
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U
影响因子：
8.3
作者：
HEISS, WD
通讯作者：
HEISS, WD
DOI：
10.1007/978-3-319-57193-5_16
发表时间：
2017-01-01
期刊：
NEURODEGENERATIVE DISEASES: PATHOLOGY, MECHANISMS, AND POTENTIAL THERAPEUTIC TARGETS
影响因子：
--
作者：
Fan, Jing;Dawson, Ted M.;Dawson, Valina L.
通讯作者：
Dawson, Valina L.
DOI：
10.1073/pnas.1508249112
发表时间：
2016-01-05
影响因子：
11.1
作者：
Chen, Cho-Yi;Logan, Ryan W.;McClung, Colleen A.
通讯作者：
McClung, Colleen A.