Lemborexant Reduces Infarct Volume and Improves Long-Term Functional Recovery in a Murine Model of Ischemic Stroke.

Introduction: Recovery following ischemic stroke is highly variable and often incomplete, underscoring the urgent need to develop novel targeted poststroke treatments. While the mechanisms underlying poststroke recovery remain incompletely understood, sleep fragmentation, a common consequence of stroke, has been linked to worse patient outcomes. Lemborexant is a dual orexin receptor antagonist that promotes sleep by suppressing wakefulness and enhancing sleep continuity. We hypothesized that lemborexant would reduce poststroke sleep disturbances and promote recovery in a rodent model of stroke. Methods: We examined the effects of lemborexant (10 mg/kg and 30 mg/kg) and zolpidem (30 mg/kg) on sleep macrostructure, fragmentation, and EEG spectra in both healthy mice and in stroke model mice, which underwent photothrombotic ischemia of the forelimb somatosensory cortex. We also evaluated whether 12 days of drug administration altered infarct volume and functional recovery following the experimental induction of stroke in model mice. Results: Lemborexant treatment (30 mg/kg) increased the percentage of NREM sleep, while preserving sleep continuity, in both healthy and stroke model mice. In contrast, zolpidem increased NREM sleep after stroke, but also increased sleep fragmentation in both groups. Lemborexant treatment at 10 mg/kg and 30 mg/kg significantly reduced infarct volume eight weeks after the induction of stroke. In addition, lemborexant-treated mice showed greater use of the impaired limb four weeks after stroke. Interpretation: These preclinical findings suggest that lemborexant stabilizes sleep and promotes structural and functional recovery following the experimental induction of stroke in model mice, supporting its potential as a novel therapeutic intervention following ischemic stroke.