Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy

Authors

  • Gabi Dezsi,

    1. Department of Medicine (Royal Melbourne Hospital), Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
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  • Ezgi Ozturk,

    1. Department of Medicine (Royal Melbourne Hospital), Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
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  • Davor Stanic,

    1. Florey Neurosciences Institutes, Parkville, Victoria, Australia
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  • Kim L. Powell,

    1. Department of Medicine (Royal Melbourne Hospital), Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
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  • Hal Blumenfeld,

    1. Departments of Neurology, Neurobiology and Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A
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  • Terence J. O'Brien,

    1. Department of Medicine (Royal Melbourne Hospital), Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
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  • Nigel C. Jones

    Corresponding author
    • Department of Medicine (Royal Melbourne Hospital), Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
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Address correspondence to Nigel C. Jones, Department of Medicine, Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, 4th Floor Clinical Sciences Building, Royal Parade, Parkville, Vic., Australia, 3052. E-mail: ncjones@unimelb.edu.au

Summary

Purpose

Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has been reported to have disease-modifying antiepileptogenic activity in the WAG/Rij rat model of genetic generalized epilepsy (GGE) with absence seizures. Here we examined whether chronic treatment with ESX (1) possesses antiepileptogenic effects in the genetic absence epilepsy rats from Strasbourg (GAERS) model of GGE, (2) is associated with a mitigation of behavioral comorbidities, and (3) influences gene expression in the somatosensory cortex region where seizures are thought to originate.

Methods

GAERS and nonepileptic control (NEC) rats were chronically treated with ESX (in drinking water) or control (tap water) from 3 to 22 weeks of age. Subsequently, all animals received tap water only for another 12 weeks to assess enduring effects of treatment. Seizure frequency and anxiety-like behaviors were serially assessed throughout the experimental paradigm. Treatment effects on the expression of key components of the epigenetic molecular machinery, the DNA methyltransferase enzymes, were assessed using quantitative polymerase chain reaction (qPCR).

Key Findings

ESX treatment significantly reduced seizures in GAERS during the treatment phase, and this effect was maintained during the 12-week posttreatment phase (p < 0.05). Furthermore, the anxiety-like behaviors present in GAERS were reduced by ESX treatment (p < 0.05). Molecular analysis revealed that ESX treatment was associated with increased expression of DNA methyltransferase enzyme messenger RNA (mRNA) in cortex.

Significance

Chronic ESX treatment has disease-modifying effects in the GAERS model of GGE, with antiepileptogenic effects against absence seizures and mitigation of behavioral comorbidities. The cellular mechanism for these effects may involve epigenetic modifications.

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