Acute administration of a dual orexin receptor antagonist attenuates sleep fragmentation in a mouse model of traumatic brain injury.

Abstract

Traumatic brain injuries (TBI) induce persistent sleep dysregulation. We aimed to determine if a dual orexin receptor antagonist (DORA) could improve sleep dysregulation acutely in mice after TBI across multiple timepoints after an injury to mimic as needed clinical interventions. Male and female C57BL/6J mice (N = 5-8 per treatment group) received a TBI by controlled cortical impact or sham surgery (SHAM). Sleep architecture was assessed at baseline and after vehicle (VEH) or DORA (Lemborexant) given by gavage 24 hours (H), 2 weeks (W), 1 month (M), or 2 M post-TBI. TBI produced increases in non-rapid eye movement sleep (NREMS) amounts and waking EEG delta, theta, and alpha power 24 H post-injury compared to baseline measures and reductions in these measures 1-2 months post-injury. TBI-DORA condition had no effect on acute TBI sleep amount and EEG power effects. However, increased waking frequencies were observed at 1 M in the TBI-VEH group during the light period and were not significantly different from baseline at 1 M in the TBI-DORA group, suggesting an effect on sleep fragmentation. A return to baseline NREMS was also observed in TBI-DORA groups at 1 M looking at average NREMS duration across Zeitgeber Time (ZT) during the light period. DORA treatment reduced sleep latency during the multiple sleep latency test (MSLT) in all groups. Overall, these data suggest that acute interventional DORA treatment can inhibit persistent sleep fragmentation and reverse increased wakefulness after TBI.