Circadian Rhythms in Ischemic Stroke: From Molecular Pathways to Chronotherapeutic Strategies

Circadian rhythms - endogenous 24-h oscillations - shape the risk, pathophysiology, and recovery of ischemic stroke. Diurnal variation in stroke onset, severity, and treatment responsiveness reflects clock control over cardiovascular tone, hemostasis, immune activity, neurovascular integrity, and metabolic homeostasis. After a stroke, circadian misalignment can blunt repair programs, amplify neuroinflammation, and accelerate cognitive decline.

We synthesize how circadian mechanisms act across the neurovascular unit to modulate neuronal excitability, receptor and transport cycles, glial reactivity, endothelial barrier function, hemostasis/fibrinolysis, and glymphatic clearance. Particular emphasis is placed on the ischemic penumbra, where intrinsic (BAX/BCL-2-regulated) and extrinsic death-receptor pathways show time-of-day sensitivity that influences salvageability. We link post-stroke circadian disruption to proteostasis and amyloid-β handling, providing a mechanistic bridge to long-term cognitive impairment. We also reconcile treatment-timing data, including biological phase (e.g., PAI-1/tPA rhythms, blood-brain barrier permeability), and operational factors jointly shape outcomes for thrombolysis and endovascular therapy. Finally, we outline chronotherapeutic avenues - light, melatonin, time-targeted pharmacology, personalized rehabilitation - and candidate biomarkers to guide timing.

The circadian phase is a key determinant of stroke susceptibility, tissue vulnerability, and recovery potential. Integrating chronobiology into prevention, reperfusion, and rehabilitation enables time-tailored strategies that align interventions with intrinsic rhythms, thereby improving outcomes and reducing disability.