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

Jung, H. R.; Venkitaraman, S.; Blackwood, S. L.; Kamal, A.; Jiang, Y.; Lee, J.; Lee, D.; Bibi, N.; Ibrahim, K. M.; Yuede, C. M.; Lee, J.-M.; Landsness, E. C.

doi:10.64898/2025.12.02.691079

bioRxiv · 10.64898/2025.12.02.691079

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

Jung, H. R.·Venkitaraman, S.·Blackwood, S. L.·Kamal, A.·Jiang, Y.·Lee, J.·Lee, D.·Bibi, N.·Ibrahim, K. M.·Yuede, C. M.·Lee, J.-M.·Landsness, E. C.

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Abstract

IntroductionRecovery 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. MethodsWe 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. ResultsLemborexant 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. InterpretationThese 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. Summary for Social Media if PublishedO_LIIf you and/or a co-author has a X handle that you would like to be tagged, please enter it here. (format: @AUTHORSHANDLE). @EricLandsness C_LIO_LIWhat is the current knowledge on the topic? Sleep plays a critical role in structural and functional recovery after stroke, but most pharmacologic sleep aids, such as benzodiazepines and zolpidem, can fragment sleep and impair neuroplasticity. Dual orexin receptor antagonists like lemborexant may offer a newer, mechanistically distinct approach with potential neuroprotective benefits. C_LIO_LIWhat question did this study address? This study investigated whether the dual orexin receptor antagonist lemborexant could improve sleep quality, reduce ischemic injury, and enhance functional recovery following stroke in adult mice, compared with the sleep-promoting agent zolpidem. C_LIO_LIWhat does this study add to our knowledge? Lemborexant increased NREM sleep without causing fragmentation, reduced infarct volume, and improved motor recovery when administered. These findings suggest that modulating sleep architecture through orexin antagonism during the subacute phase after stroke can promote neural repair and functional recovery. C_LIO_LIHow might this potentially impact on the practice of neurology? Since lemborexant is already FDA-approved for insomnia, these results could be rapidly translated into a therapeutic opportunity to improve stroke recovery through targeted sleep modulation. This approach may shift poststroke care toward integrating neurorestorative, sleep-based interventions during the subacute phase. C_LI

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Jung, H. R., Venkitaraman, S., Blackwood, S. L., Kamal, A., Jiang, Y., Lee, J., Lee, D., Bibi, N., Ibrahim, K. M., Yuede, C. M., Lee, J.-M., Landsness, E. C.. 2025-12-05. Lemborexant Reduces Infarct Volume and Improves Long-Term Functional Recovery in a Murine Model of Ischemic Stroke. https://doi.org/10.64898/2025.12.02.691079

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