Epigenetic histone deacetylase inhibition by sodium butyrate reduces neuroinflammation, improves neurological dysfunction and promotes disease modification of epileptogenesis following traumatic brain injury

Post-traumatic epilepsy (PTE) is a chronic and debilitating seizure disorder that arises following traumatic brain injury (TBI) and is characterized by persistent neuroinflammation, epigenetic dysregulation, long-term neurological deficits, and recurrent seizures. Despite its clinical significance, there are currently no effective therapies that halt epileptogenesis and improve functional outcomes after TBI. Targeting epigenetic mechanisms, particularly histone deacetylation, represents a promising therapeutic strategy. Histone deacetylase (HDAC) inhibitors, such as sodium butyrate (SB), modulate gene expression by preserving histone acetylation in neurons and glial cells, thereby influencing gene networks and pathways involved in epileptogenesis. Using a controlled cortical impact model in adult male mice, we evaluated the effects of SB (600 mg/kg for 21 days post-injury) on neuroinflammation, epilepsy development, and long-term behavioral outcomes. Seizure progression and epileptogenic biomarkers were assessed by continuous 24/7 video-EEG monitoring for 4 months and the seizure threshold was assessed by 6-Hz test for 4 months post-injury. SB treatment effectively normalized TBI-induced HDAC hyperactivity, significantly reduced both acute and chronic neuroinflammation, reduced inhibitory interneuron loss, enhanced hippocampal neurogenesis, reduced mossy fiber sprouting and markedly alleviated cognitive and affective neuropsychiatric impairments. Although SB did not alter the overall incidence of PTE, it significantly increased seizure threshold, reduced seizure frequency, and attenuated key epileptogenic biomarkers, indicating a meaningful modification of disease progression. These results support that SB, by targeting injury-induced HDAC hyperactivation during the latent period, interrupts maladaptive epigenetic and neuroinflammatory cascades, thereby reducing progression to chronic epilepsy and neurological dysfunction. Collectively, these findings demonstrate HDAC inhibition as a viable neuroprotective and disease-modifying strategy, offering a promising therapeutic avenue to mitigate epilepsy burden and improve neurological recovery following TBI.