Lemborexant reduces infarct volume and improves long-term functional recovery in a murine Model of Ischemic stroke

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. 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. Lemborexant treatment
(30mg/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. 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.