Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy
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eLife assessment
Sodium selenate reduced seizures when administered after initiation of epilepsy, complementing earlier work showing efficacy if administered before initiation. The novelty of the results is not much more than the earlier study. Sodium selenate reduced phospho-tau and increased PP2A protein expression, and reversed TLE-associated telomere-shortening. However, whether these effects were critical to the reduced seizures is not clear. Finally, proteome and metabolome data from the animal model of epilepsy is discussed and provide initial insights into the effects of sodium selenate treatment on molecular pathology, however, the data are not well developed so revisions along these lines will be important so conclusions can be made.
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Abstract
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.
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eLife assessment
Sodium selenate reduced seizures when administered after initiation of epilepsy, complementing earlier work showing efficacy if administered before initiation. The novelty of the results is not much more than the earlier study. Sodium selenate reduced phospho-tau and increased PP2A protein expression, and reversed TLE-associated telomere-shortening. However, whether these effects were critical to the reduced seizures is not clear. Finally, proteome and metabolome data from the animal model of epilepsy is discussed and provide initial insights into the effects of sodium selenate treatment on molecular pathology, however, the data are not well developed so revisions along these lines will be important so conclusions can be made.
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Reviewer #1 (Public Review):
It has been shown that selenium protects against the development of epilepsy, and behavioral comorbidities, as pointed out by the authors. This paper attempts to show it does if administered later after chronic seizures start. While clinically relevant, as noted by the authors, the paper seems not to be a major advance beyond the prior study. The antiseizure effect is also not very convincing because the effect size is so small and the variance so high. The data about behavior is more convincing but similar data were in the previous paper, so it is not very novel.
The data showing changes in PP2A are interesting and while logical that it contributes to the effects of sel, one would like to see proof that this is the basis of sel effects. Same for hyperphosphorylated tau, telomere length, etc. The doubt is …
Reviewer #1 (Public Review):
It has been shown that selenium protects against the development of epilepsy, and behavioral comorbidities, as pointed out by the authors. This paper attempts to show it does if administered later after chronic seizures start. While clinically relevant, as noted by the authors, the paper seems not to be a major advance beyond the prior study. The antiseizure effect is also not very convincing because the effect size is so small and the variance so high. The data about behavior is more convincing but similar data were in the previous paper, so it is not very novel.
The data showing changes in PP2A are interesting and while logical that it contributes to the effects of sel, one would like to see proof that this is the basis of sel effects. Same for hyperphosphorylated tau, telomere length, etc. The doubt is because these are indices that change after many types of experiments and they change many aspects of brain and peripheral physiology. Regarding molecular data, how these provide insight and comparison to other data sets of this kind would be valuable.
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Reviewer #2 (Public Review):
Casillas-Espinosa et al. present a well-designed study to evaluate the validity of sodium-selenate treatment in chronic epilepsy. Previous studies from the same group identified increased phospho-tau in models of seizures and epilepsy, which can be pharmacologically addressed through activation of protein phosphatase 2A with sodium-selenate. Here the authors tested the effect of delayed treatment with sodium selenate in the post-KA SE rat TLE model. Sodium selenate stopped the progression of seizures during and beyond a 4-week treatment phase compared to Levitiracetam and vehicle-treated animals. Sodium selenate further improved cognitive and sensorimotor impairments. It also persistently reduced phospho-tau and increased PP2A protein expression, and reversed TLE-associated telomere-shortening. Finally, …
Reviewer #2 (Public Review):
Casillas-Espinosa et al. present a well-designed study to evaluate the validity of sodium-selenate treatment in chronic epilepsy. Previous studies from the same group identified increased phospho-tau in models of seizures and epilepsy, which can be pharmacologically addressed through activation of protein phosphatase 2A with sodium-selenate. Here the authors tested the effect of delayed treatment with sodium selenate in the post-KA SE rat TLE model. Sodium selenate stopped the progression of seizures during and beyond a 4-week treatment phase compared to Levitiracetam and vehicle-treated animals. Sodium selenate further improved cognitive and sensorimotor impairments. It also persistently reduced phospho-tau and increased PP2A protein expression, and reversed TLE-associated telomere-shortening. Finally, proteome and metabolome data from the model is discussed and provides initial insights into sodium selenate treatment's molecular consequences.
This study validates the use of sodium selenate as a promising pharmacological treatment in experimental TLE that reduces seizure burden and restores cognitive deficits and pathomolecular changes. The specific strength of the study is a clinically relevant treatment paradigm, starting when recurrent seizures are fully established, and the antiepileptogenic effect with a sustainable reduction in seizure burden even after discontinuation of treatment.
The conclusions of this paper are mostly well supported by data, but some aspects of the proteome and metabolome data analysis need to be clarified and extended. The molecular data appears to be the weakest part of this study and would have benefited from adjusted sample sizes to account for interindividual variability between animals and the complex multi-dimensional nature of the data.
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Author Response
Reviewer #1 (Public Review):
It has been shown that selenium protects against the development of epilepsy, and behavioral comorbidities, as pointed out by the authors. This paper attempts to show it does if administered later after chronic seizures start. While clinically relevant, as noted by the authors, the paper seems not to be a major advance beyond the prior study. The antiseizure effect is also not very convincing because the effect size is so small and the variance so high. The data about behavior is more convincing but similar data were in the previous paper, so it is not very novel.
Thank you for reviewing our paper. Previous work has shown that sodium selenate, not selenium, can delay the appearance of seizures and mitigate behavioural comorbidities if given immediately after the epileptogenic brain insult, …
Author Response
Reviewer #1 (Public Review):
It has been shown that selenium protects against the development of epilepsy, and behavioral comorbidities, as pointed out by the authors. This paper attempts to show it does if administered later after chronic seizures start. While clinically relevant, as noted by the authors, the paper seems not to be a major advance beyond the prior study. The antiseizure effect is also not very convincing because the effect size is so small and the variance so high. The data about behavior is more convincing but similar data were in the previous paper, so it is not very novel.
Thank you for reviewing our paper. Previous work has shown that sodium selenate, not selenium, can delay the appearance of seizures and mitigate behavioural comorbidities if given immediately after the epileptogenic brain insult, but before the appearance of spontaneous recurring seizures (i.e. before epilepsy development), i.e. is anti-epileptogenic. The novelty of our current work is that we are treating once epilepsy develops, i.e. is disease-modifying. This is the first time a pharmacological agent has been shown to be disease-modifying in established epilepsy, resulting in an enduring reduction in seizures suppression even after treatment withdrawal, as well as to mitigate the behavioural comorbidities that commonly are co-morbid with chronic epilepsy. This is potentially ground-breaking new findings for the epilepsy field, as at present the only current disease-modifying therapy for established chronic epilepsy is epilepsy surgery.
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