In diabetic neuropathy, activation of axonal and sensory neuronal degeneration pathways leads to distal axonopathy. The NAD+-dependent deacetylase enzyme, Sirtuin 1 (SIRT1), can prevent activation of these pathways. Chandrasekaran et al. show that increased expression of SIRT1 in sensory neurons prevents and reverses experimental diabetic neuropathy induced by a high-fat diet.
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.
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