Epigenetic mechanisms, such as alterations in
histone acetylation based on
histone deacetylases (HDACs) activity, have been linked not only to normal brain function but also to several
brain disorders including
epilepsy and the epileptogenic process. In WAG/Rij rats, a genetic model of
absence epilepsy, epileptogenesis and mild-depression comorbidity, we investigated the effects of two
HDAC inhibitors (HDACi), namely
sodium butyrate (NaB),
valproic acid (VPA) and their co-administration, on the development of absence
seizures and related psychiatric/neurologic comorbidities following two different experimental paradigms. Treatment effects have been evaluated by EEG recordings (EEG) and behavioural tests at different time points. Prolonged and daily VPA and NaB treatment, started before
absence seizure onset (P30), significantly reduced the development of
absence epilepsy showing antiepileptogenic effects. These effects were enhanced by NaB/VPA co-administration. Furthermore, early-chronic HDACi treatment improved depressive-like behaviour and cognitive performance 1 month
after treatment withdrawal. WAG/Rij rats of 7 months of age showed reduced acetylated levels of
histone H3 and H4, analysed by Western Blotting of homogenized brain, in comparison to WAG/Rij before seizure onset (P30). The brain
histone acetylation increased significantly during treatment with NaB or VPA alone and more markedly during co-administration. We also observed decreased expression of both HDAC1 and 3 following HDACi treatment compared to control group. Our results suggest that histone modifications may have a crucial role in the development of
epilepsy and early treatment with HDACi might be a possible strategy for preventing epileptogenesis also affecting behavioural comorbidities.