HDAC6 inhibition enhances peroxiredoxin 1 acetylation to mitigate oxidative stress and seizure activity in focal cortical dysplasia.

BACKGROUND: Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy (DRE) which is characterized by malformations of the cortex and molecular dysregulation. Despite advancements in classification and surgical interventions the pathophysiology behind it remains unclear and non-surgical treatment options remain limited. Oxidative stress, induced by imbalances of reactive oxygen species (ROS) and antioxidant defences, has been involved in the pathophysiology of FCD. This study evaluates the role of histone deacetylase 6 (HDAC6) in modulating oxidative stress and seizure activity through the acetylation status of peroxiredoxin-1 (Prdx1), a key antioxidant enzyme.

METHODS: Cortical samples from FCD Type II patients and BCNU rat model were analysed using qRT-PCR, immunoblotting, and co-immunoprecipitation to assess the expression of HDAC6, and acetylation status of Prdx1. ROS levels were measured using dichlorofluorescin diacetate (DCFDA) assay. Pharmacological inhibition of HDAC6 using Tubastatin A (TubA) was evaluated for its effects on oxidative stress, Prdx1 acetylation, and seizure activity induced by pilocarpine.

RESULTS: HDAC6 was found to be significantly upregulated in the cortical samples from FCD Type II tissues and BCNU rats. Increased HDAC6 activity reduced Prdx1 acetylation, leading to elevated ROS levels and oxidative stress. TubA treatment restored Prdx1 acetylation, reduced oxidative stress, and significantly decreased seizure frequency and increased seizure latency in the BCNU model.

CONCLUSION: This study identifies HDAC6 as a key regulator of oxidative stress and epileptogenesis in FCD through Prdx1 deacetylation. Pharmacological inhibition of HDAC6 offers a promising therapeutic strategy for managing FCD-associated epilepsy by restoring antioxidant defences and mitigating seizure activity. Further studies are warranted to explore its clinical potential.