Licastro, Ester (2025) Exploring Time-of-Day Influences on Neuroprotective Strategies: New Insights from an Experimental In Vivo Stroke Model. [Tesi di dottorato]

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Abstract

Annually, more than 15 million people suffer from a stroke accident, with 5 million dying and another 5 million remaining permanently disabled. Emerging evidence suggests that impairment of the glymphatic system — a brain-wide clearance network that relies on aquaporin-4 dynamics — may play a critical role in its development. Consistently, neuroprotective strategies aimed to counteract the cascade of event following an ischemic insult has shown remarkable neuroprotective potential. Among them, remote conditioning activates endogenous protective mechanisms involving both neural and humoral pathways that transmit signals from the limb to the brain. Despite extensive experimental and clinical efforts, most pharmacological agents have failed to demonstrate efficacy in human stroke trials. Among the many contributing factors, the timing of stroke onset may critically influence therapeutic outcomes. Although both preclinical and clinical data show promise, the effectiveness of remote ischemic postconditioning in treating acute stroke in humans remains uncertain. Therefore, this work is divided in two sections aiming to provide new insight in stroke field. Specifically, the study aims to: • To unravel the mechanisms by which glymphatic dysfunction and remote ischemic conditioning interact in the pathogenesis of stroke, with the final goal of identifying novel therapeutic strategies to enhance fluid clearance and improve stroke recovery. • To establish whether circadian differences represent a potential reason for translational difficulties and can modulate the protective effect of RIC depending on the time of day of its application. The data obtained in this work, supports the remote conditioning strategy as a promising non-invasive intervention to elicit neuroprotection, by restoring AQP4 polarization at astrocytic end-feet and improving glymphatic clearance, thus counteracting glymphatic impairments post-stroke. The study further highlights the influence of circadian biology on stroke intervention, suggesting the potential use of remote conditioning for tailoring a specific subset of patience experiencing stroke during sleep phase. The timing of intervention represents a critical factor of therapeutic outcome, emphasizing the importance of considering individual circadian biology when developing and optimizing neuroprotective strategies.

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