LAUSR

STUDY OBJECTIVES Traumatic brain injury (TBI) can result in posttraumatic epilepsy (PTE) and sleep disturbances. We hypothesized that treatment with sleep aids after TBI can ameliorate PTE. METHODS CD-1 mice underwent controlled cortical impact (CCI), sham injury or no craniotomy. Sham and CCI groups underwent a month-long daily treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol) or a respective vehicle starting on the day of CCI. We performed continuous EEG (electroencephalography) recordings at week-1 and months-1, 2 and 3 for ~1 week each time. Seizure analysis occurred at all-time points and sleep analysis occurred in week-1 and month-1/2 in all groups. Subsets of CCI and sham groups were subjected to voltage-clamp experiments in hippocampal slices to evaluate GABAergic synaptic inhibition. RESULTS DORA-22 treatment suppressed seizures in month 1-3 recordings. TBI reduced amplitude and frequency of miniature inhibitory synaptic currents (mIPSCs) in dentate granule cells and these changes were rescued by DORA-22 treatment. Sleep analysis showed that DORA-22 increased non-rapid eye movement (NREM) sleep during lights-off whereas THIP increased REM sleep during lights-on in week-1. Both treatments displayed subtle changes in time spent in NREM or REM at month-1/2 as well. TBI increased normalized EEG delta power (NΔ) at week-1 and month-1, but also resulted in loss of the homeostatic diurnal oscillation of NΔ, which was restored by DORA-22 but not THIP treatment. CONCLUSIONS Dual orexin antagonists may have a therapeutic potential in suppressing PTE potentially by enhancing GABAergic inhibition and impacting sleep homeostatic drive.