Epigenetic Histone Deacetylation Inhibition Prevents the Development and Persistence of Temporal Lobe Epilepsy

Abstract

Epilepsy is a chronic brain disease characterized by repeated unprovoked seizures. Currently, no drug therapy exists for curing epilepsy or disease modification in people at risk. Despite several emerging mechanisms, there have been few studies of epigenetic signaling in epileptogenesis, the process whereby a normal brain becomes progressively epileptic because of precipitating factors. Here, we report a novel role of histone deacetylation as a critical epigenetic mechanism in epileptogenesis. Experiments were conducted using the histone deacetylase (HDAC) inhibitor sodium butyrate in the hippocampus kindling model of temporal lobe epilepsy (TLE), a classic model heavily used to approve drugs for treatment of epilepsy. Daily treatment with butyrate significantly inhibited HDAC activity and retarded the development of limbic epileptogenesis without affecting after-discharge signal. HDAC inhibition markedly impaired the persistence of seizure expression many weeks after epilepsy development. Moreover, subchronic HDAC inhibition for 2 weeks resulted in a striking retardation of epileptogenesis. HDAC inhibition, unexpectedly, also showed erasure of the epileptogenic state in epileptic animals. Finally, butyrate-treated animals exhibited a powerful reduction in mossy fiber sprouting, a morphologic index of epileptogenesis. Together these results underscore that HDAC inhibition prevents the development of TLE, indicating HDAC's critical signaling role in epileptogenesis. These findings, therefore, envisage a unique novel therapy for preventing or curing epilepsy by targeting the epigenetic HDAC pathway.

Measuring Histone Deacetylase Inhibition in the Brain

“…HDAC inhibitors are important tools for unraveling the pathology and mechanistic basis of brain diseases. There are many HDAC inhibitors that are used in animals, such as TSA, sodium butyrate, vorinostat (SAHA), valproic acid, and entinostat (MS-275) (Reddy et al, 2018;Ververis, Hiong, Karagiannis, & Licciardi, 2013). Sodium butyrate is widely used for broad-spectrum HDAC inhibition and consequent augmentation and acetylation of H3 and H4 histone proteins in the brain (Deutsch et al, 2008;Ferrante et al, 2003;Takuma et al, 2014).…”

“…Sodium butyrate is a short chain fatty acid inhibitor of class I and II HDACs. This dose of sodium butyrate is neuroprotective in a mouse model of temporal lobe epileptogenesis (Reddy et al., ); therefore, the same regimen was selected for the present study to determine the extent of HDAC inhibition. At 4 h and 24 hr post‐TBI, brain tissues were flash frozen and dissected for the cerebral cortex.…”

“…Aberrant expression of epigenetic factors, such as an extreme increase or decrease in histone marks (such as acetyl groups), can result in increased or decreased gene expression, respectively, and lead to genetic syndromes and altered cellular function (Carey & La Thangue, 2006). The inhibition of different HDAC proteins has been reported to be beneficial in neurological conditions such as Alzheimer's disease (Lee et al, 2018), Huntington's disease (Bassi, Tripathi, Monziani, Di Leva, & Biagioli, 2017), traumatic brain injury (TBI; Wong & Langley, 2016), depression (Covington, Maze, Vialou, & Nestler, 2015), epilepsy (Reddy, Clossen, & Reddy, 2018), cancer (Rajendran et al, 2015), and neuropathic pain (Descalzi et al, 2015). Due to the neuroprotective effects of some HDAC inhibitors, this evolving drug class has been increasingly evaluated as potential therapeutic agents for central nervous system (CNS) diseases (Huang, Doherty, & Dingledine, 2002;Younus & Reddy, 2017).…”

“…It was recently reported that HDAC inhibition is associated with effective disease‐modification of epileptogenesis (Clossen & Reddy, ; Reddy et al., ). Epilepsy is a complex disease state that can be triggered by a precipitating injury such as a traumatic brain injury, yet the extent of epigenetic modification following such incidents is still unknown.…”

“…Thus, HDAC inhibitors may hold great potential as antiepileptogenic agents for curing epilepsy and for investigating the resulting changes in epigenetic regulation of gene expression. Sodium butyrate has been identified as one such compound that may retard the process of epileptogenesis (Reddy et al., ). Sodium butyrate inhibits a broad range of HDACs in the brain (Davie, ; Ferrante et al., ; Takuma et al., ).…”