Hyperactivation of Epigenetic HDAC Pathway in an Experimental Model of Acquired Epilepsy
Abstract number :
214
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2020
Submission ID :
2422561
Source :
www.aesnet.org
Presentation date :
12/6/2020 12:00:00 PM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Victoria Golub, Texas A&M University Health Science Center; Doodipala Samba Reddy - Texas A&M University Health Science Center College of Medicine;
Rationale:
Epigenetic signaling regulates a diverse set of neuronal processes, both salubrious and pathological, including learning and memory, normal aging, and maladaptive epileptogenic cascades. Emerging evidence suggests the involvement of epigenetic histone deacetylase (HDAC) pathway in regulation of neuroinflammation and synaptic plasticity following CNS insult, though the underlying mechanisms are unclear. In this study, we sought to test hypothesis that traumatic brain injury (TBI) activates the HDAC pathway in the brain and thereby contributes to the development of acquired post-traumatic epilepsy (PTE).
Method:
A severe form of TBI was induced by the controlled cortical impact (CCI) model in mice. Hippocampal and cortical brain tissue samples were collected at various time points after TBI. The HDAC inhibitor, sodium butyrate (600 mg/kg), was administered for 21 days (latency period of PTE). HDAC activity levels were estimated by the Boc-Lys(Ac) HDAC enzyme assay. Enzyme-linked immunoassays (ELISA) were used for estimating cytokine levels in groups with or without HDAC inhibition therapy. Immunohistochemistry for astrocytes (GFAP) and microglia (IBA1) was performed at days 1, 7, and 30 post-injury to visualize the extent of microglial activation.
Results:
TBI induced a significant (p< 0.01) increase in HDAC activity in both the cortex and hippocampus as early as 4 hr post-injury and persisted for 30-days. Sodium butyrate treatment resulted in a significant (~70%) decrease in TBI-induced HDAC hyperactivation. Immunohistochemistry for astrocyte and microglia markers revealed a strong peak in microgliosis at 7 days after TBI, which was attenuated by butyrate therapy. IBA1 expression levels were also reduced by butyrate therapy. The neuroinflammation outcomes were correlated with reduced lesion volume in the PTE model.
Conclusion:
These results confirm our scientific premise of maladaptive epigenetic responses manifested as hyperactivation of the epigenetic HDAC pathway after TBI, which is a leading cause of PTE. Targeted epigenetic modulation represents a promising intervention for PTE and its comorbidities in people at risk for PTE.
Funding:
:**Funded by DOD Award #W81XWH-16-1-0660**
Basic Mechanisms