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Effects of Histone Deacetylase Inhibitors on the Development of Epilepsy and Psychiatric Comorbidity in WAG/Rij Rats

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Abstract

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.

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This work was supported by the Italian Ministry of University and Research (MIUR), Prot N° 2015XSZ9A2. This work was partly supported by the Italian Ministry of Health, Grant N° GR-2013-02355028.

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  1. Department of Health Science, School of Medicine, University of Catanzaro, Via T. Campanella, 115, 88100, Catanzaro, Italy

    Rita Citraro, Antonio Leo, Carmen De Caro, Valentina Nesci, Martina Tallarico, Emilio Russo & Giovambattista De Sarro

  2. Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy

    Maria E. Gallo Cantafio & Nicola Amodio

  3. Department of Pharmacy, University of Naples Federico II, Naples, Italy

    Giuseppina Mattace Raso, Adriano Lama, Roberto Russo & Antonio Calignano

  4. Pharmacology Section, CNR, Institute of Neurological Sciences, Roccelletta di Borgia, Catanzaro, Italy

    Martina Tallarico

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Citraro, R., Leo, A., De Caro, C. et al. Effects of Histone Deacetylase Inhibitors on the Development of Epilepsy and Psychiatric Comorbidity in WAG/Rij Rats. Mol Neurobiol 57, 408–421 (2020). https://doi.org/10.1007/s12035-019-01712-8

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