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

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.

Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study

“…16 Animal studies have shown that shortened TL increases seizure frequency. 15,45 However, the results of these studies may not be consistent with the results of the MR studies for several reasons. Firstly, the two animal studies used different species and introduced seizures in an artificial way, making it difficult to extrapolate the findings to humans accurately.…”

“…Observational studies have shown that TL is shortened in patients with epilepsy 16 . Animal studies have shown that shortened TL increases seizure frequency 15,45 . However, the results of these studies may not be consistent with the results of the MR studies for several reasons.…”

“…11,12 TL varies across different tissues, commonly measured in white blood cells, 10 and has been associated with neurodegenerative diseases. 13,14 Animal studies have demonstrated a negative correlation between TL and seizures, 15 and observational studies have shown telomere shortening in patients with drug-resistant epilepsy. 16 However, traditional statistical methods have limitations in establishing causal relationships, as potential confounders and reverse causality cannot be completely ruled out.…”

Diurnal circadian clock gene expression is altered in models of genetic and acquired epilepsy

“…There is strong evidence that repeated perturbation of liver circadian function can lead to metabolic disruption 48 and reports of altered systemic metabolic profiles in KASE rats, which persist even after ASM treatment. 25 There are some data suggesting lowered clock gene expression is associated with increased epileptogenesis 49 and some evidence indicating reduced clock gene rhythms in the pilocarpine-induced post-SE model of TLE. 50 Importantly, genetic deletion of the Bmal1 gene reduced the electrically induced seizure threshold in knockout mice compared with wild-type mice, suggesting that Bmal1 contributes to epileptic excitability.…”

“…As previously described, 11-week-old male Wistar rats (n = 40) underwent a modified low-dose KA intraperitoneal administration protocol. 24,25 Age-matched (sham, n = 40) controls were handled the same way during the same experimental session as the KASE rats did not receive KA but receive intraperitoneal saline injection (1 mL/ kg) instead. Following the initial injection of KA (7.5 mg/ kg ip), the rats were monitored for 45 min for behavioral seizures by an experimenter blinded to the drug administration (KA or saline) using the Racine scale.…”