Abstract
Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.
Highlights
Stroke, caused by a sudden interruption to the blood supply of the brain, has a wide range of detrimental consequences that have contributed to its recognition as the leading cause of disability and second most common cause of death worldwide
Exposure to light during the early dark phase results in increased Per2 expression in the shell of the suprachiasmatic nucleus (SCN) whereas light exposure late in the dark phase increases Per1 expression in the shell of the SCN, leading to a phase delay or phase advance in activity rhythms, respectively (Yan and Silver, 2004). This activation of Per paralogs occurs through CREB/MAPK signaling acting on cAMP-response elements (CRE) in Per promoters (Travnickova-Bendova et al, 2002).The functions of mammalian cellular clock proteins are regulated through posttranslational modifications through various kinases, methylation, polyadenylation, histone modifications, and noncoding RNAs (Cardone et al, 2005; Mendoza-Viveros et al, 2017; Okamoto-Uchida et al, 2019)
Mutations in Circadian Locomotor Output Cycles Kaput (Clock) increased the total and active PAI1 levels along with reduced tissue plasminogen activator (tPA) in plasma (Westgate et al, 2008). These results suggest that core clock genes are involved in regulating expression of key components in hemostasis and the fibrinolytic system, leading to an increased risk for the development of prothrombotic phenotypes and an increased risk for cerebrovascular events
Summary
Stroke, caused by a sudden interruption to the blood supply of the brain, has a wide range of detrimental consequences that have contributed to its recognition as the leading cause of disability and second most common cause of death worldwide. Circadian Disruption Alters Stroke Outcome plasminogen to plasmin, which acts as a key player in fibrinolysis This protease has been used as a rapid and effective treatment during ischemic strokes by initiating reperfusion of the affected brain region, the therapeutic efficacy is limited to a 3–4.5-h time window from stroke onset (Cheng and Kim, 2015). Endogenous biological rhythms, modulated through external cues such as light, are important for adapting to predictable changes in the environment and maintaining internal physiology, which suggests the importance of time of day on health (Lowrey and Takahashi, 2000; Golombek and Rosenstein, 2010; Patke et al, 2020). Other external cues, including feeding, physical activity, and social cues, have the capacity to entrain circadian rhythms as well, but generally less effectively as light (Aschoff et al, 1971; Stephan, 2002; Lewis et al, 2018)
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