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Potential circadian effects on translational failure for neuroprotection
Elga Esposito1, Wenlu Li1, Emiri T Mandeville1
1Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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.
Insights
Circadian rhythms impact stroke neuroprotection. Treatments effective in rodent models failed in humans because rodent and human stroke phases differ, affecting treatment efficacy and brain injury.
Area of Science:
- Neuroscience
- Chronobiology
- Stroke Research
Background:
- Neuroprotective strategies successful in rodent stroke models often fail in human clinical trials.
- Opposing circadian cycles between nocturnal rodents and diurnal humans may explain this translational gap.
- Most human strokes occur during the active daytime phase, contrasting with nocturnal rodent activity cycles.
Purpose of the Study:
- To investigate the role of circadian phase in the efficacy of neuroprotective strategies for stroke.
- To determine if differing circadian cycles between rodents and humans contribute to the failure of stroke treatments in clinical translation.
- To evaluate the impact of circadian rhythm on brain tissue vulnerability and treatment response in experimental stroke models.
Main Methods:
- Tested three neuroprotective agents (normobaric hyperoxia, α-phenyl-butyl-tert-nitrone (αPBN), MK801) in rodent focal cerebral ischemia models.
- Compared treatment efficacy in day-time (inactive phase) versus night-time (active phase) rodent stroke models.
- Utilized laser-speckle imaging to assess the cerebral ischemia penumbra and TUNEL staining for cell death.
- Investigated molecular mechanisms in primary mouse neurons under circadian-like cycles, assessing glutamate and reactive oxygen species release, and apoptotic/necroptotic mediator activation.
Main Results:
- All tested neuroprotective treatments reduced infarction in inactive-phase rodent stroke models but not in active-phase models.
- Active-phase rodent stroke models exhibited a narrower ischemic penumbra and reduced infarct growth.
- Neurons in the active phase showed less glutamate and reactive oxygen species release, and lower apoptotic/necroptotic signaling under oxygen-glucose deprivation.
- αPBN and MK801 only reduced neuronal death in inactive-phase neurons.
Conclusions:
- Circadian rhythm significantly influences the efficacy of neuroprotective treatments in experimental stroke models.
- The differing circadian phases between rodents and humans are a critical factor in the translational failure of stroke therapies.
- Future translational studies for stroke and other central nervous system diseases must account for the influence of circadian rhythms on treatment outcomes.
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