小柯机器人

昼夜节律也会影响药物的功能
2020-06-04 16:36

美国哈佛医学院Eng H. Lo研究小组的最新工作表明,昼夜节律会影响神经保护药物的转化研究。这一研究成果于2020年6月3日在线发表在《自然》上。

研究人员发现,夜间活动的啮齿动物与日间活动的人类具有相反的昼夜节律周期,这可能会导致转换研究失败。研究人员在局灶性脑缺血的小鼠和大鼠模型中测试了三种独立的神经保护方法:常压高氧、自由基清除剂αPBN和N-甲基-D-天冬氨酸(NMDA)拮抗剂MK801。这三种治疗均能减少白天(非活动期)中风啮齿动物模型的梗塞,但不能减少夜间(活跃期)中风啮齿动物模型的梗塞,这与大多数临床卒中发生的阶段(活跃、白天)相匹配。
 
激光散斑成像显示,在活动期小鼠模型中,脑缺血的半影区比在活动期模型中窄。较小的半影与较低的TUNEL阳性染色细胞密度相关,并且梗死面积从12小时减少到72小时。当研究人员在原代小鼠神经元中诱导昼夜节律样循环时,“活动状态”与“非活动状态”相比,氧气和葡萄糖的缺乏触发了谷氨酸盐和活性氧的释放量减少,而凋亡和坏死性介导因子的活化程度也更低。αPBN和MK801仅在“非活动期”神经元中减少神经元死亡。
 
这些发现表明,对于中风和中枢神经系统疾病的转化研究,必须考虑昼夜节律对神经保护的影响。
 
据了解,一些在中风的啮齿动物模型中起作用的神经保护剂,仍未能在临床试验中提供相应保护。
 
附:英文原文

Title: Potential circadian effects on translational failure for neuroprotection

Author: Elga Esposito, Wenlu Li, Emiri T. Mandeville, Ji-Hyun Park, Ikbal encan, Shuzhen Guo, Jingfei Shi, Jing Lan, Janice Lee, Kazuhide Hayakawa, Sava Sakadi, Xunming Ji, Eng H. Lo

Issue&Volume: 2020-06-03

Abstract: 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 humans1,2 may contribute to this failure in translation. We tested three independent neuroprotective approaches—normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), 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. 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 diseases.

DOI: 10.1038/s41586-020-2348-z

Source: https://www.nature.com/articles/s41586-020-2348-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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