Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy

Pablo M Casillas-Espinosa; Alison Anderson; Anna Harutyunyan; Crystal Li; Jiyoon Lee; Emma L Braine; Rhys D Brady; Mujun Sun; Cheng Huang; Christopher K Barlow; Anup D Shah; Ralf B Schittenhelm; Richelle Mychasiuk; Nigel C Jones; Sandy R Shultz; Terence J O'Brien

doi:10.7554/eLife.78877

eLife (Mar 2023)

Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy

Pablo M Casillas-Espinosa,
Alison Anderson,
Anna Harutyunyan,
Crystal Li,
Jiyoon Lee,
Emma L Braine,
Rhys D Brady,
Mujun Sun,
Cheng Huang,
Christopher K Barlow,
Anup D Shah,
Ralf B Schittenhelm,
Richelle Mychasiuk,
Nigel C Jones,
Sandy R Shultz,
Terence J O'Brien

Affiliations

Pablo M Casillas-Espinosa: ORCiD; Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Monash Proteomics & Metabolomics Facility and Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
Alison Anderson: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Anna Harutyunyan: ORCiD; Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Crystal Li: Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Jiyoon Lee: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
Emma L Braine: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Rhys D Brady: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Mujun Sun: Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Cheng Huang: Department of Neurology, The Alfred Hospital, Commercial Road,, Melbourne, Victoria, Australia
Christopher K Barlow: Department of Neurology, The Alfred Hospital, Commercial Road,, Melbourne, Victoria, Australia
Anup D Shah: Department of Neurology, The Alfred Hospital, Commercial Road,, Melbourne, Victoria, Australia
Ralf B Schittenhelm: Department of Neurology, The Alfred Hospital, Commercial Road,, Melbourne, Victoria, Australia
Richelle Mychasiuk: Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Nigel C Jones: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Sandy R Shultz: ORCiD; Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
Terence J O'Brien: ORCiD; Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Monash Proteomics & Metabolomics Facility and Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

DOI: https://doi.org/10.7554/eLife.78877
Journal volume & issue: Vol. 12

Abstract

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There are no pharmacological disease-modifying treatments with an enduring effect to mitigate the seizures and comorbidities of established chronic temporal lobe epilepsy (TLE). This study aimed to evaluate for disease modifying effects of sodium selenate treatment in the chronically epileptic rat post-status epilepticus (SE) model of drug-resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, animals received sodium selenate, levetiracetam, or vehicle subcutaneousinfusion continuously for 4 weeks. To evaluate the effects of the treatments, one week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of epilepsy disease severity in our current study. The results showed that sodium selenate treatment was associated with mitigation of measures of disease severity at 8 weeks post-treatment cessation; reducing the number of spontaneous seizures (p< 0.05), cognitive dysfunction (p< 0.05), and sensorimotor deficits (p< 0.01). Moreover, selenate treatment was associated with increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening (p< 0.05). Network medicine integration of multi-omics/pre-clinical outcomes identified protein-metabolite modules positively correlated with TLE. Our results provide evidence that treatment with sodium selenate results in a sustained disease-modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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