Circadian Effects in the Stroke Penumbra

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Circadian Effects in the Stroke Penumbra Almost all rodent stroke research is performed in the daytime. For nocturnal rodents, this is their inactive (non- awake) phase. In humans, more ischemic strokes occur during the daytime, and almost all patients in neuroprotection trials are also recruited in the daytime. But for diurnal humans, this is their active (awake) phase. We hypothesize that this “circadian mismatch” contributes to translational problems in stroke. Our preliminary data (some published in Esposito et al, Nature 2020) suggest that: (i) neuroprotection may be more difficult in active phase versus inactive phase stroke; (ii) the penumbra may evolve differently in active phase versus inactive phase stroke; and (iii) vascular regulation and cell death mechanisms may be affected by circadian rhythm. From a clinical perspective, the two important aspects of the stroke penumbra are blood flow and infarct progression. Therefore, we will pursue 4 integrated aims to investigate circadian effects on flow and cell death in the penumbra. In Aim 1, we will map penumbral blood flow, metabolism, cellular response, tissue injury and behavioral outcomes in mouse focal cerebral ischemia across the entire sinusoidal cycle of circadian rhythm. In Aim 2, we will map the effects of cerebral ischemia on central and peripheral circadian rhythms during stroke evolution. In Aim 3, we test the hypothesis that the circadian gene Bmal1 regulates endothelial shear stress that underlies hemodynamic response in the penumbra. In Aim 4, we test the hypothesis that Bmal1 regulates glutamate reuptake transporters, antioxidant gene expression, and anti-apoptotic mediators that underlie circadian influences on excitotoxicity, oxidative stress and apoptosis. Circadian biology affects almost all aspects of physiology, disease, and response to therapies (Cederroth et al, Cell Metab 2019). This project may represent the first step in what should be a larger effort to re-assess experimental stroke and neurovascular unit mechanisms with the “correct” circadian context.