Dual orexin antagonist normalized sleep homeostatic drive, enhanced GABAergic inhibition, and suppressed seizures after traumatic brain injury

Abstract

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.

Subthalamic nucleus stimulation attenuates motor seizures via modulating the nigral orexin pathway

“…In addition, orexin, another focus of this study, is secreted by a group of neurons in the hypothalamus that are located closest to the STN and project to the STN and SNr (Peyron et al, 1998). Several studies have found that the orexin pathway plays a vital role in various seizures (Samzadeh et al, 2020;Celli and Luijtelaar, 2022;Konduru et al, 2022). Previous studies have observed the expression and co-localization of OX1R and OX2R in the STN and SNr (Korotkova et al, 2002;Li et al, 2019).…”

Sleep, inflammation, and hemodynamics in rodent models of traumatic brain injury

“…After CCI, mice have identifiable gliosis and changes in sleep and EEG delta power ( Willie et al, 2012 ; Hazra et al, 2014 ; Thomasy et al, 2017 ; Thomasy and Opp, 2019 ; Konduru et al, 2021 , 2022 ). Another study found that EEG delta power during NREM sleep decreased by 55% after CCI at 7 days post-injury, and theta power (5.5–8.5 Hz) increased 59% during REM sleep.…”