Disruptions of Circadian Rhythms and Thrombolytic Therapy During Ischemic Stroke Intervention

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.

Keywords: circadian rhythm; TPA; hemorrhagic transformation; light at night (LAN); prothrombotic state; stroke; thrombolysis (tPA); time of day.

FIGURE 1

(A) Light entrains the circadian clock. The light-dark cycle is the strongest zeitgeber, involved in synchronizing intrinsic circadian oscillations in the brain and periphery. Light energy in the form of photons enter the retina, depolarizing intrinsically photosensitive retinal ganglion cells (ipRGCs) which relay photic information via the retinohypothalamic tract to the so-called master circadian pacemaker, the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. Direct and indirect projections of the SCN entrain other regions including local nuclei within the mediobasal hypothalamus (MBH), the paraventricular nucleus (PVN), paraventricular nuclei of the thalamus (PVT), arcuate nucleus (Arc). Endocrine signals from the pituitary gland and the pineal (melatonin secretion) that are initiated by the SCN provide time of day information to entrain peripheral oscillators. (B) Exposure to light at night disrupts the molecular circadian clock. The molecular clock in the cells of central and peripheral tissues is comprised of transcriptional-translational feedback loops. The positive arm of the core circadian feedback loop involves the protein products of the genes circadian locomotor output cycles kaput (CLOCK) and brain and muscle arnt-like protein-1 (BMAL1), which heterodimerize in the cytoplasm, translocate to the nucleus, and bind to the E-box promotor regions of Period (Per) and Cryptochrome (Cry), driving their transcription. In the negative feedback arm of the core circadian feedback loop (not shown) Per/Cry protein products translocate to the nucleus to repress CLOCK/BMAL transcriptional activation, cycling with a period lasting approximately 24 h (please see Hurley et al., 2016; Rumanova et al., 2020) for further details on the molecular circadian clock). Exposure to light during the night disrupts Per1 expression resulting in altered circadian amplitude and phase.

FIGURE 2

Time of Day Influences Ischemic Stroke. A time of day variation exists in the onset and frequency of stroke, factors contributing to cerebral ischemia, and the efficacy of thrombolytic medication administration. A morning surge of blood pressure, fibrinolytic agents, and platelet activation coincide with increased stroke onset. In contrast, the frequency of ischemic events is reduced during the evening, along with a reduced risk for hemorrhagic transformation and improved function with tPA intervention. This suggests a potential chronopharmacological therapeutic target for optimized treatment intervention that could improve patient outcome based on the time of ischemic event. Tissue plasminogen activator (tPA) plasminogen activator inhibitor-1 (PAI-1), plasmin-alpha-2-antiplasmin complex (PAP), thrombin-antithrombin complex (TAT).