Dual orexin antagonist DORA-22 suppressed posttraumatic seizures and enhances GABAergic inhibition in dentate granule cells

Abstract

Background: 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 craniotomy or no craniotomy. Sham and CCI groups underwent a month-long treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol). We performed week-long EEG recordings during week-1 of treatment and again at months 1, 2 and 3. Seizure analysis occurred at all-time points and sleep analysis occurred in week-1 and month-1 recordings in all groups. Subsets of animals in sleep aid-treated and untreated CCI, and sham groups were subjected to voltage clamp experiments. Results: DORA-22 treated group had seizures at week-1 but none at months 1-3. 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 sleep (NREM) in the first 4hours of lights-off whereas THIP increased REM sleep in the first 4-hours of lights-on in week-1, At month-1 both treatments reduced time in NREM during lights-off. TBI increased NREM delta power (NΔ) along with loss of the homeostatic overnight decline of NΔ in week-1 regardless of treatment. DORA-22 and THIP treatment restored NΔ to levels similar to no craniotomy animals at month-1. Conclusions: DORA-22 treatment suppressed posttraumatic seizures possibly due to enhanced GABAergic inhibition in dentate granule cells. DORA-22 may have therapeutic potential in suppressing PTE.