Translational Studies of Epigenetic Interventions for Post-Traumatic Epilepsy
Abstract
Post-traumatic epilepsy (PTE) is a life-long seizure disorder that can arise from traumatic brain injury (TBI). In addition to the rapid inflammatory response and lesion-site necrosis, TBI induces immediate and long-term changes within the epigenome which contribute to the development of post-traumatic seizures. Animal models of PTE have many limitations to demonstrate a high enough incidence of seizures to design studies which test novel therapeutic strategies. Using a controlled-cortical impact model of severe TBI, we designed a model of PTE which has generated spontaneous seizures in about 80% of mice. In the first aim of this dissertation, we fully characterized the histopathology, electrographic activity, and behavioral changes which are associated with PTE over 120 days after TBI incident.
Currently, there are no pharmacotherapies in use to favorably control seizures, and/or the functional and behavioral outcome of PTE. Epigenetic histone modification can be easily manipulated with the use of HDAC inhibitors which block the removal of acetyl groups from histone proteins, thereby affecting gene transcription. Previous research using HDAC inhibitor compounds have reported neuroprotective effects such as reduction of both inflammation and cell loss. In aims 2 and 3 of this dissertation, we investigated the effects of dietary, broad-spectrum, and narrow-spectrum HDAC inhibitors improve neurological and cognitive outcomes after TBI. Our broad HDAC inhibitor compounds were sodium butyrate and vorinostat (SAHA); we chose entinostat (previously MS-275) as a narrow spectrum inhibitor.
Our results demonstrate that HDAC inhibitor administration normalizes HDAC activity levels to non-injured mice, and results in decreased inflammation, reduced neurodegeneration, and improved quality of life. All HDAC inhibitor compounds reduced seizure burden in a significant fashion. Sodium butyrate reduced frequency and duration of seizures in responding mice, providing a scientific basis of HDAC inhibition as a disease modifier in epileptogenesis. SAHA and entinostat treatments also demonstrated a significant reduction in seizure frequency, but more importantly, we also observed a reduction in the incidence of chronic epilepsy in these cohorts.
Our findings indicate that HDAC inhibition therapy given soon after TBI can be potentially neuroprotective and may be a viable therapeutic to prevent or reduce epileptogenesis after TBI in at-risk patients.
Subject
EpilepsyPost-Traumatic Epilepsy
Traumatic Brain Injury
Epigenetics
HDAC inhibition
Neuroscience
Inflammation
Neurodegeneration
Seizures
EEG
Citation
Golub, Victoria (2021). Translational Studies of Epigenetic Interventions for Post-Traumatic Epilepsy. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /195343.