Editor's evaluation: Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy

Abstract

Full text Figures and data Side by side Abstract Editor's evaluation eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics 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. Editor's evaluation This important study provided evidence that sodium selenate is a treatment that reduces the symptoms of chronic seizures in a rat model of epilepsy. The improved symptoms were reduced seizure frequency, improved memory, and improved sensorimotor function. The authors provided convincing evidence that even after treatment ended the benefits persisted, a remarkable finding. They also identified several possible mediators of the effects, including PPAR and h-tau, as well as telomere length. An in-depth study of potential genetic regulation by selenate provided additional possible targets of selenate that ameliorate epilepsy. https://doi.org/10.7554/eLife.78877.sa0 Decision letter Reviews on Sciety eLife's review process eLife digest According to the World Health Organization (WHO), there are around 50 million people with epilepsy worldwide. Although drugs are available to control epileptic seizures, these only provide symptomatic relief. They cannot prevent the condition from worsening, and if people with epilepsy stop taking their medication, there is no lasting effect on the severity or frequency of their seizures. Some epilepsy cases are also resistant to these drugs. This is particularly common in adults with temporal epilepsy, with 30% of people continuing to suffer with seizures despite receiving medication. Current treatments also have no effect on problems with learning, memory and mental health that sometimes accompany drug-resistant epilepsy. Previous studies in animals have identified some potential treatments that could slow the progression of temporal epilepsy, but these have only been shown to work when used at a very early stage. Since most individuals with temporal epilepsy have already started having seizures when they are diagnosed (and it is difficult to predict who will develop the condition), these drugs are unlikely to be useful in practice. Here, Casillas-Espinosa et al. set out to find if a novel drug called sodium selenate can stop the progression of epilepsy and reduce the severity of temporal epilepsy when the condition is fully advanced. To do this, they used an animal model of temporal epilepsy, where rats had been modified to develop spontaneous seizures, resistance to normal anti-seizure medications, and problems with learning and memory. Casillas-Espinosa et al. found that sodium selenate not only reduced the number and severity of seizures in these model rats, but also improved their memory and learning ability. Several rats stopped having seizures altogether even after the treatment had stopped, indicating that sodium selenate had a long-lasting protective effect. Genetic analysis of the rats also revealed that shorter telomeres (special DNA sequences at the ends of chromosomes) correlated with increasing severity of the condition, suggesting that telomere length could help predict who might develop temporal epilepsy or respond best to treatment. This study identifies sodium selenate as a potential treatment that could reverse the progression of temporal epilepsy, even in individuals with advanced symptoms. Later this year, sodium selenate will be trialled in people with drug-resistant temporal epilepsy to determine if the drug benefits humans in the same way. Casillas-Espinosa et al. hope that it will improve participants’ epilepsy and, ultimately, their quality of life. Introduction Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy in adults and is frequently accompanied by disabling neuropsychiatric and cognitive comorbidities (Hermann et al., 2008; Hermann et al., 2000; Kwan et al., 2011; Sharma et al., 2007; Tellez-Zenteno et al., 2007). People with epilepsy are often required to take multiple anti-seizure medications (ASMs) in an attempt to control their seizures. However, these treatments are ineffective at controlling seizures in more than 30% of cases (Hermann et al., 2008; Hermann et al., 2000; Kwan et al., 2011; Sharma et al., 2007; Tellez-Zenteno et al., 2007), and can cause significant adverse side effects (Alonso-Vanegas et al., 2013; Perucca and Gilliam, 2012; Taylor et al., 2011). Current ASMs are merely symptomatic and do not mitigate the severity, progression, or outcome of the epilepsy, and if the patient ceases the medication their seizures are just as severe and frequent as if the person has never taken the medication in the first place (Simonato et al., 2014). Despite decades of research and development, the more than 20 new ASMs that have been introduced to clinical practice have failed to reduce the proportion of people with epilepsy who have drug-resistant seizures (Chen et al., 2018). Moreover, the cognitive and neuropsychiatric comorbidities that are prevalent in these patients remain difficult to treat and are not improved by the ASM treatment (Hinnell et al., 2010; Valente and Busatto Filho, 2013). Animal studies have identified compounds potentially capable of delaying epileptogenesis (i.e. the process by which a non-epileptic brain turns into an epileptic one), but to date, these have only been demonstrated to be effective when the treatment is initiated early in the disease process (i.e. immediately after the brain insult) (Casillas-Espinosa et al., 2019b; Liu et al., 2016; Pauletti et al., 2019; Rizzi et al., 2019; Zeng et al., 2009; Huang et al., 2019). Because the majority of TLE patients already have established epilepsy when they present to the clinic (Foster et al., 2019), and there are no reliable biomarkers to predict who will develop TLE, this treatment strategy has limited clinical utility (Simonato et al., 2021). Surgical resection of the epileptogenic zone is currently the only effective disease-modifying intervention in patients with chronic drug-resistant TLE, but is only suitable in selected patients, is not always successful, and can have significant complications (Téllez-Zenteno et al., 2005). It is estimated that <5% of patients with drug-resistant epilepsy are suitable for resective epilepsy surgery (Téllez-Zenteno et al., 2005). Thus, there is a compelling need to identify pharmacological DMTs that are effective in patients with chronic TLE. (O’Brien et al., 2013; Sharma et al., 2007; Simonato et al., 2013). Hyperphosphorylated tau (h-tau) is a neuropathological hallmark of several neurodegenerative conditions and has recently been implicated in epileptogenesis (Casillas-Espinosa et al., 2020; Ittner and Götz, 2011; Johnstone et al., 2015; Liu et al., 2016; Sen et al., 2007; Shultz et al., 2015; Thom et al., 2011; van Eersel et al., 2010). For example, h-tau is present in the brains of rodents with TLE, (Corcoran et al., 2010b; Jones et al., 2012; Shultz et al., 2015) ,and deposits of h-tau have been identified in surgically resected tissue from patients with drug-resistant epilepsy (Puvenna et al., 2016; Sánchez et al., 2018; Sen et al., 2007; Tai et al., 2016; Thom et al., 2011). The primary tau phosphatase in the brain (i.e. an enzyme that dephosphorylates tau) is protein phosphatase 2 A (PP2A) (Corcoran et al., 2010a), a heterotrimer consisting of a catalytic C subunit, a scaffold A subunit, and a regulatory B subunit with variable isoforms (Janssens and Goris, 2001). In several models of epilepsy, activation of PP2A with sodium selenate has been shown to reduce h-tau, and early treatment imparts anti-epileptogenic effects, while also reducing behavioral deficits associated with the epilepsy (Liu et al., 2016). However, whether pharmacological intervention with sodium selenate in chronic epileptic animals is a DMT remains to be determined. Therefore, this study investigated the effect of sodium selenate treatment on epileptic and behavioral outcomes, as well as multi-omics network medicine and bioinformatics approaches to uncover relevant molecular pathways, in chronically epileptic rats. We used the well-validated kainic acid (KA) post- post-status epilepticus (SE) model of TLE, where animals develop resistance to drug treatment, behavioral, cognitive, and sensorimotor comorbidities analogous to human drug-resistant TLE (Casillas-Espinosa et al., 2019b; Thomson et al., 2020). Results This study evaluated the effect of sodium selenate on established TLE, using the post-SE model of drug-resistant TLE. Ten-weeks post-SE, chronically epileptic rats were randomly assigned to receive either sodium selenate (1 mg/kg/day), levetiracetam (200 /mg/kg/day, a commonly prescribed ASM for TLE) (Mbizvo et al., 2012), or vehicle (saline 0.9%) continuously for four weeks. To evaluate the sustained effects of the treatments, video-EEG was acquired before, during, and up to eight weeks post-treatment, followed by behavioral tests to assess cognitive, and sensorimotor comorbidities. Targeted and untargeted proteomics and metabolomics were performed on brain tissue to investigate potential pathways and molecules associated with modified disease outcomes. Telomere length was investigated as a surrogate marker of disease severity and treatment response. The experimental paradigm is shown in Figure 7 of the Methods section. Sodium selenate is disease-modifying with enduring effects that reduce the number of seizures in drug-resistant TLE rats Video-electroencephalogram (vEEG) was used to examine the effects of the treatments before, during, and up to eight weeks post-treatment on the occurrence of spontaneous recurrent seizures (Figure 1). Vehicle and levetiracetam-treated animals showed a significant progressive increase in the number of seizures recorded over the course of the experiments [F (8, 124)=2.022, p<0.05]. vEEG analysis during continuous drug treatment (10–14 weeks post-SE) revealed that neither vehicle, sodium selenate, or levetiracetam significantly impacted the number [F (4, 62)=0.4781, p=0.751], duration [F (2, 43)=0.5030, p=0.608], or severity of the seizures [F (2, 43)=0.4563, p=0.636], experienced by post-SE rats, indicating that drug-resistant epilepsy is present 10 weeks after KA-induced SE (Figure 1A). However, following the cessation of treatment, one-way ANOVA showed a treatment effect reducing the number of seizures that the animal experienced [F (31, 31)=3.956, p<0.0001; Figure 1A]. Tukey’s post hoc analysis revealed that sodium selenate treatment significantly reduced the number of seizures eight weeks post-treatment in contrast to vehicle-treated animals (p<0.05). Interestingly, four of the twelve sodium selenate-treated animals did not manifest any seizures eight weeks after the drug washout, while all of the vehicle and levetiracetam-treated animals showed spontaneous seizures through the experiment. In contrast, Tukey’s post hoc showed that levetiracetam treatment did not significantly reduce the number of seizures in comparison to vehicle or selenate-treated animals. Average seizure duration [F (1, 15)=1.038, p=0.3243; Figure 1B] and seizure severity, assessed by the Racine scale (Racine, 1972) [F (1, 13)=0.4873, p=0.497; Figure 1C] were not significantly different between the three treatment groups. Figures showing the individual timepoints of the seizure analysis are found in Figure 1—figure supplement 1. Figure 1 with 1 supplement see all Download asset Open asset Sodium selenate has a sustained effect to reduce spontaneous seizures in the post-KA SE rat model of chronic drug-resistant temporal lobe epilepsy (TLE). (A) Sodium selenate stopped the progression of seizures from treatment week four and significantly reduced seizure frequency eight weeks after the last day of treatment compared to vehicle-treated animals (B) average seizure duration and (C) seizure severity was not significantly different between the three treatment groups; (* significantly different from vehicle p<0.05). LEV levetiracetam. Two-way ANOVA with Dunn’s post hoc. Tx- treatment, wk week, WO, washout. Data shown as mean ± SEM. Post-SE +Vehicle (n=10), Post-SE +selenate (n=12), and Post-SE +levetiracetam (n=12). (D) Representative EEG example of an animal presenting a spontaneous seizure, 120 s window, low pass 70 Hz, high pass 1 Hz; arrows represent seizure start and seizure ends. Sodium selenate treatment improves spatial memory and recognition memory Cognitive deficits are one of the most debilitating comorbidities seen in patients with TLE (Hermann et al., 2008; Hermann et al., 2000; Kwan et al., 2011; Sharma et al., 2007; Tellez-Zenteno et al., 2007). The novel object placement (NOP) evaluates spatial memory (Spanswick and Sutherland, 2010). Vehicle-treated animals had impaired spatial memory in comparison to shams, as they spent significantly less time in the novel location of the object (p<0.05, Figure 2A). Levetiracetam treatment did not improve spatial memory compared to vehicles. Animals that had been treated with sodium selenate, even after an eight week washout, spent significantly more time evaluating the novel location of the object than those treated with the vehicle, which is indicative of improved spatial memory (p<0.05). The novel object recognition (NOR) evaluates recognition memory (Spanswick and Sutherland, 2010). Both vehicle and levetiracetam-treated rats spent less time evaluating the novel object relative to sham rats (p<0.05, Figure 2B), which is indicative of impaired recognition memory. In contrast, sodium selenate treatment was also able to improve recognition memory in comparison to vehicle-treated rats (p<0.05). Interestingly, the performance of the sodium selenate-treated animals was comparable to shams in both the NOP and NOR. Figures showing the individual timepoints of the MWM are found in Figure 2—figure supplement 1. Figure 2 with 2 supplements see all Download asset Open asset Sodium selenate improves cognitive and sensorimotor impairments in the post-KA SE rat model of chronic drug-resistant temporal lobe epilepsy (TLE). (A) Novel object placement (NOP). Vehicle and levetiracetam-treated animals showed a significantly reduced time examining the novel location of the object compared to shams. In contrast, sodium selenate treatment improved spatial memory in comparison to the vehicle in post-SE rats. (B) Novel object recognition (NOR). Post-SE animals treated with vehicle or levetiracetam showed significantly impaired recognition memory to shams. Sodium selenate rats spent more time evaluating the novel object introduced into the arena in contrast to the vehicle, which is a measure of improved recognition memory. (C) Post-SE rats treated with vehicle and levetiracetam had significantly longer search time in the water maze acquisition session in contrast to shams. (D) Water maze reversal, all of the post-SE rats showed significantly longer search times in comparison to the sham. For presentation purposes, data for water maze search time is graphed in blocks of two trials. (E) Post-SE rats treated with vehicle and levetiracetam exhibited more slips and falls on the beast compared to shams. In contrast, treatment with sodium selenate significantly reduced these impairments compared to the vehicle. (*p<0.05, **p<0.01, ***p<0.001; ##p<0.05, and ###p<0.001 significantly different to shams). Kruskal-Wallis with Dunn’s post hoc for the NOP and NOR. MWM two-way repeated measures ANOVA, with Dunnett’s post hoc. One-way ANOVA with Tukey’s post hoc for the beam task. Data are shown as mean ± SEM. To further evaluate cognitive function, rats were tested in the Morris water maze (MWM) (Morris, 1984). During the acquisition session of the MWM, only the post-SE rats treated with vehicle and levetiracetam displayed significantly increased search times than their sham counterparts [subject x treatment effects: F(12, 164)=2.501, p<0.01; selenate animals p>0.05 Figure 2C]. One day after the water maze acquisition session, rats underwent MWM reversal session where the location of the escape platform was changed. Here, all of the post-SE rats cohorts took more time to find the hidden platform in comparison to shams [F(4, 157)=5.971 p<0.001 Figure 2D]. No differences in swim speed were observed between the different groups. Sodium selenate treatment improves balance in drug-resistant TLE rats Rats were tested on the beam task to assess balance and coordination as a measure of sensorimotor function, which is commonly affected in people with drug-resistant TLE (Carter et al., 1999; Carter et al., 2001; Liu et al., 2016). Post-SE rats treated with sodium selenate displayed improved sensorimotor function compared to the vehicle as indicated by significantly fewer slips and falls (p<0.01, Figure 2E). In contrast, both vehicle and levetiracetam-treated animals showed significantly more slips and falls compared to shams (p<0.001 and p<0.05, respectively). The time to traverse the beam was not significantly different between the groups. No significant findings were observed in either the open field or elevated plus maze tests of anxiety-like behavior. The results of the sucrose preference test are shown in Figure 2—figure supplement 2. The protein phosphatase family is differentially expressed after treatment with sodium selenate Sodium selenate has been described to activate PP2A subunit B and to reduce h-tau after traumatic brain injury and in different models of epilepsy (Liu et al., 2016; Shultz et al., 2015). However, to further understand the mechanism by which sodium selenate exerts its disease-modifying effects in our model of established chronic TLE, we utilized state-of-the-art, high-resolution data-independent acquisition mass-spectrometry (DIA-MS), untargeted proteomics and metabolomics analyzes were carried out in the somatosensory cortex and hippocampus to identify potential markers of TLE and on the proteome and metabolome. A total of 5615 and 5538 proteins have been identified and quantified across all samples in the somatosensory cortex and hippocampus, respectively, considering a false discovery rate (q-value) cut-off of 1%. Differential expression analyses using ANOVA revealed 24 proteins in the somatosensory cortex and 9 proteins in the hippocampus to be significantly dysregulated across all experimental conditions (Figure 3, Supplementary file 1 and Supplementary file 2). Notably, protein phosphatase 2 regulatory subunit B alpha (Ppp2r5a), heat shock protein family A member 2 (Hspa2), and lymphocyte cytosolic protein 1 (Lcp1) were differentially expressed between selenate and vehicle-treated post-SE groups in the somatosensory cortex (Tukey’s HSD, FDR <0.05, Figure 3A, Supplementary file 1). Heat shock protein family B member 1 (Hspb1), Ro690 Y RNA binding protein (Ro60), and DENN domain containing 11 (Dennd11) proteins were differentially expressed between selenate and vehicle treated groups in the hippocampus (Tukey’s HSD, FDR <0.05, Figure 3B, Supplementary file 2). To further examine the changes in the proteomic profile of selenate-treated rats we performed quantitative gene set enrichment analysis between all pairs of treatment groups. Figure 3—figure supplement 1 shows the top 25 differentially regulated pathways in the somatosensory cortex (Figure 3—figure supplement 1A) and hippocampus (Figure 3—figure supplement 1B). Interestingly in the somatosensory cortex of the selenate group, among the most significantly upregulated pathways were signaling cascades mediated by activated insulin-like growth factor receptors (IGFR) and fibroblast growth factor receptors (FGRF) such as the FGFR-mediated phosphatidylinositol 3-kinase (PI-3K) cascade activation and IGFR1 signaling cascades (FDR <0.05). Among the top downregulated pathways in the somatosensory cortex were beta-oxidation of fatty acids and iron uptake and transport. Figure 3 with 3 supplements see all Download asset Open asset Differential expression analysis of all detected proteins in (A) somatosensory cortex and (B) hippocampus of all post-SE treatment groups and shams. One-way ANOVA was used to identify the difference in protein abundance among selenate, levetiracetam, and vehicle-treated groups and shams. Difference between specific groups was determined via Tukey’s honestly significant difference (HSD) test. Significance threshold was set to FDR <0.05, and significantly different proteins are labeled red. In addition to proteomic analyses, we also performed untargeted univariate metabolomic analyses on the same samples. However, we were not able to identify significant changes between the experimental groups in the somatosensory cortex, suggesting that selenate primarily induces proteomic alterations in this region whilst keeping the metabolome stable (Supplementary file 3). In contrast, six metabolites were significantly different in selenate-treated animals as shown in Supplementary file 4. Partial least squares-discriminant analysis (PLS-DA) and principal component analysis (PCA) for the proteomics and metabolomics analyses are shown in Figure 3—figure supplement 2. Sodium selenate treatment persistently reduces h-tau and increases PP2A protein expression To further validate the modification of the h-tau pathway by sodium selenate in established TLE, we performed targeted protein analysis of h-tau and PP2A in the somatosensory cortex only due to tissue availability. Semi-automated western blots showed that sodium selenate treatment persistently reduced h-tau compared to vehicle and levetiracetam-treated animals (p<0.01 for both comparisons, Figure 3—figure supplement 3A). Similarly, PP2A protein expression was significantly increased in selenate-treated animals compared to vehicle (p<0.01), levetiracetam (p<0.01), and shams (p<0.05, Figure 3—figure supplement 3B). No significant differences were found in total tau protein expression. Sodium selenate-treated animals have longer telomere lengths Telomere length was investigated as a surrogate marker of epilepsy severity and response to pharmacological treatment (Chan et al., 2020; Galletly et al., 2017; Kang et al., 2020; Lukens et al., 2009). Ear biopsies were taken 25 weeks post-SE to evaluate the effects of chronic epilepsy on telomere length. We found that TLE resulted in telomere shortening in vehicle-treated rats (p<0.001), and this was not prevented by levetiracetam treatment (p<0.01). However, sodium selenate treatment was able to reverse telomere shortening seen in post-SE animals treated with the vehicle (p<0.01), with the treated rats having telomere lengths similar to sham animals (Figure 4). Figure 4 Download asset Open asset Sodium selenate prevents telomere shortening in drug-resistant temporal lobe epilepsy (TLE) rats. Chronic post-SE rats treated with levetiracetam and vehicle showed significantly reduced telomere length in comparison to sham. In contrast, sodium selenate-treated animals had significantly longer telomeres in comparison to the vehicle. kbp, kilobase pairs (*p<0.05, **p<0.01). One-way ANOVA with Tukey’s post hoc. Data are shown as mean ± SEM. Seizure burden is correlated with shorter telomeres and poorer cognitive and sensorimotor outcomes We also investigated the relationship between the seizure burden (i.e. number of seizures per day) at the end of the eight week post-treatment washout period, with the different outcomes of the behavioral tests and TL. We found that the number of seizures was inversely correlated with the preference for the novel object in the NOR (r=–0.497, p<0.001), NOP (r=–0.357, p=0.016), and TL (r=–0.554, p=0.005). The number of seizures was correlated with the search time in the MWM (r=0.436, p=0.003) and the number of slips and falls in the beam task (r=0.762, p=0.001). Network medicine integration highlights discrete protein-metabolite modules correlate with treatment and pre-clinical outcomes Network medicine integration was performed to investigate pathways correlated with the TLE phenotype. We integrated the untargeted multi-omics (proteomics and metabolomics) datasets with the targeted proteomics and phosphoproteomics (PP2A, tau, and h-tau), TLE phenotype (seizures, cognitive, and sensorimotor outcomes), and telomere length studies to investigate protein-metabolite groups/pathways correlated with the response to selenate treatment. Weighted correlation network analysis identified 20 and 17 protein-metabolite modules, respectively, in the hippocampal and cortical multi-omic datasets. Several protein-metabolite modules showed significant positive and negative correlations with multiple treatment groups and various clinical measures (Figure 5). Figure 5C In the hippocampal network (Figure 5A), the Purple module shows significant inverse correlation with selenate treatment group, and is enriched for proteins and metabolites involved in aminoacyl-tRNA biosynthesis (FDR = 0.0059) and Lysine degradation (FDR = 0.021) pathways. This module is also inversely correlated with levetiracetam-treated group, but shows no correlation with the vehicle group. The Yellow module is significantly (p=0.02) correlated with the selenate-treated group and has no significant correlations with other groups. This module is enriched for proteins and metabolites involved in complement cascade, oxidative phosphorylation and other metabolic pathways. Figure 5 Download asset Open asset Hippocampal and somatosensory cortex module-trait correlation heatmaps . The relationship of protein-metabolite modules (in the Y-axis) with measured clinical traits (X-axis) in (A) the hippocampus and (B) somatosensory cortex. Modules are labeled by color and representative enriched pathway. Each block of the heatmap shows the Spearman correlation coefficient (SCC) of every module with clinical traits as well as the associated P value in brackets. The SCC values range from –1 to +1, depending on the strength and direction of the correlation. In the somatosensory cortex correlation network (Figure 5B), the Tan (p=0.002), Magenta (p=0.002), Yellow (p=0.02), and Light-cyan (p=0.02) modules were significantly correlated with the selenate treated group and showed no correlation with the vehicle-treated group (Figure 5B). The magenta module does not annotate to any significant pathways; however, the Yellow module is enriched for proteins and metabolites involved in oxidative phosphorylation and other metabolic pathways, and the Tan module annotates to the insulin signaling pathway. Lastly, proteins and metabolites in the Light-cyan module are enriched for fatty acid biosynthesis pathways. Discussion Current pharmacological treatments for TLE, ASMs, are merely symptomatic, attenuating seizures when taken on an ongoing basis without any sustained disease-modifying effects on the propensity to have seizures, or on its disabling associated neuropsychiatric, cognitive, and sensorimotor comorbidities (Brooks-Kayal et al., 2013; Pitkänen et al., 2013; Saletti et al., 2019). Once these treatments are discontinued (or the patient fails to take doses), the seizures relapse to at least the same severity and frequency as pre-treatment (Coan and Cendes, 2013; Kwan et al., 2011). Here, we report for the first time a pharmacological treatment that has persistent disease-modifying effects in an animal model of chronic drug-resistant TLE. Sodium selenate treatment was shown to have an enduring effect, mitigating the established epileptic state, and reducing the frequency of seizures and cognitive comorbidities. Our group has previously shown that treatment with sodium selenate in epilepsy models reduces h-tau, increases PP2A, and mitigates the development of epilepsy when delivered immediately after an epileptogenic brain injury before the occurrence of spontaneous recurrent seizures (i.e. an anti-epileptogenic effect) (Jones et al., 2012; Liu et al., 2016). However, the most common clinical scenario is that