Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy
- Monash University, Australia
- University of Melbourne, Australia
Abstract
There are no pharmacological disease-modifying treatments that have an enduring effect to mitigate the seizures and comorbidities associated with established chronic temporal lobe epilepsy (TLE). Sodium selenate has been reported to have anti-epileptogenic effects if given before TLE onset. However, the majority of TLE patients already have established epilepsy when they present to the clinic. 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, rats were randomly assigned to receive either sodium selenate, levetiracetam, or vehicle subcutaneous infusions 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 has emerged as a potential biomarker of chronic brain conditions, 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 in both novel object placement and recognition tasks), and sensorimotor deficits (p< 0.01). Moreover, in the brain post-mortem 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 the TLE phenotype. 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.
Data availability
All the metrodology and results form this work have been included in the manuscrit or as part of the supplementary material.Data has been deposited in Dryad https://doi.org/10.5061/dryad.37pvmcvnd
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EEG and multi-omics dataDryad Digital Repository, doi:10.5061/dryad.37pvmcvnd.
Article and author information
Author details
Pablo Miguel Casillas-Espinosa
Funding
National Health and Medical Research Council (APP1087172)
- Pablo Miguel Casillas-Espinosa
University of Melbourne (603834)
- Pablo Miguel Casillas-Espinosa
CIHR Skin Research Training Centre (PTJ - 153051)
- Richelle Mychasiuk
National Health and Medical Research Council (Level 2 CDF)
- Sandy R Shultz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures were approved by the Florey Animal Ethics Committee (ethics number 16-042-UM), adhered to the Australian code for the care and use of animals for scientific purposes and consistent with ARRIVE 2.0 guidelines
Reviewing Editor
- Helen Scharfman, New York University Langone Medical Center, United States
Publication history
- Received: March 23, 2022
- Accepted: March 8, 2023
- Accepted Manuscript published: March 9, 2023 (version 1)
Copyright
© 2023, Casillas-Espinosa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy
eLife 12:e78877.
https://doi.org/10.7554/eLife.78877
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