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

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 monthlong 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 voltageclamp experiments in hippocampal slices to evaluate GABAergic synaptic inhibition. RESULTS: DORA-22 treatment suppressed seizures in month 1-3 recordings. TBI reduced the 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 nonrapid 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 not only increased normalized EEG delta power (NΔ) at week-1 and month-1 but also resulted in the 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.

The impact of cigarette smoking and nicotine on traumatic brain injury: a review.

INTRODUCTION: Traumatic Brain Injury (TBI) and tobacco smoking are both serious public health problems. Many people with TBI also smoke. Nicotine, a component of tobacco smoke, has been identified as a premorbid neuroprotectant in other neurological disorders. This study aims to provide better understanding of relationships between tobacco smoking and nicotine use and effect on outcome/recovery from TBI. METHODS: PubMed database, SCOPUS, and PTSDpub were searched for relevant English-language papers. RESULTS: Twenty-nine human clinical studies and nine animal studies were included. No nicotine-replacement product use in human TBI clinical studies were identified. While smoking tobacco prior to injury can be harmful primarily due to systemic effects that can compromise brain function, animal studies suggest that nicotine as a pharmacological agent may augment recovery of cognitive deficits caused by TBI. CONCLUSIONS: While tobacco smoking before or after TBI has been associated with potential harms, many clinical studies downplay correlations for most expected domains. On the other hand, nicotine could provide potential treatment for cognitive deficits following TBI by reversing impaired signaling pathways in the brain including those involving nAChRs, TH, and dopamine. Future studies regarding the impact of cigarette smoking and vaping on patients with TBI are needed .