Potential circadian effects on translational failure for neuroprotection

Elga Esposito, Wenlu Li, Emiri T. Mandeville, Ji-Hyun Park, Ikbal Şencan, Shuzhen Guo, Jingfei Shi, Jing Lan, Janice Lee, Kazuhide Hayakawa, Sava Sakadžić, Xunming Ji and Eng H. Lo ()
Additional contact information
Elga Esposito: Harvard Medical School
Wenlu Li: Harvard Medical School
Emiri T. Mandeville: Harvard Medical School
Ji-Hyun Park: Harvard Medical School
Ikbal Şencan: Harvard Medical School
Shuzhen Guo: Harvard Medical School
Jingfei Shi: Harvard Medical School
Jing Lan: Harvard Medical School
Janice Lee: Harvard Medical School
Kazuhide Hayakawa: Harvard Medical School
Sava Sakadžić: Harvard Medical School
Xunming Ji: Capital Medical University
Eng H. Lo: Harvard Medical School

Nature, 2020, vol. 582, issue 7812, 395-398

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2348-z

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