Sodium selenate retards epileptogenesis in acquired epilepsy models reversing changes in protein phosphatase 2A and hyperphosphorylated tau

Abstract

There are no treatments in clinical practice known to mitigate the neurobiological processes that convert a healthy brain into an epileptic one, a phenomenon known as epileptogenesis. Downregulation of protein phosphatase 2A, a protein that causes the hyperphosphorylation of tau, is implicated in neurodegenerative diseases commonly associated with epilepsy, such as Alzheimer's disease and traumatic brain injury. Here we used the protein phosphatase 2A activator sodium selenate to investigate the role of protein phosphatase 2A in three different rat models of epileptogenesis: amygdala kindling, post-kainic acid status epilepticus, and post-traumatic epilepsy. Protein phosphatase 2A activity was decreased, and tau phosphorylation increased, in epileptogenic brain regions in all three models. Continuous sodium selenate treatment mitigated epileptogenesis and prevented the biochemical abnormalities, effects which persisted after drug withdrawal. Our studies indicate that limbic epileptogenesis is associated with downregulation of protein phosphatase 2A and the hyperphosphorylation of tau, and that targeting this mechanism with sodium selenate is a potential anti-epileptogenic therapy.

Sodium selenate, a protein phosphatase 2A activator, mitigates hyperphosphorylated tau and improves repeated mild traumatic brain injury outcomes

“…Moreover, we have previously found increased expression of pS198 and pS262 after a severe TBI (Shultz et al, 2015c). Tau-5 is a marker for total tau levels (Liu et al, 2016;Shultz et al, 2015c). Therefore, the blots on PVDF were developed with anti-pS198 (1:1000; Abcam, UK), anti-pS262 (1:1000; Abcam, UK), and antiTau-5 (1:1000, Millipore, USA), as we well as anti-PR55 (1:1000, Millipore, USA), anti-PP2Ac (1:1000; Millipore, USA), and anti-GAPDH (1:5000; Cell Signaling, USA) primary antibodies overnight at 4 C. They were then incubated with secondary antibodies of respective animal species conjugated to horseradish peroxidase and visualized by enhanced chemiluminescent substrate kit (Amersham™ ECL™ Western-blotting detection reagents) and exposure to x-films.…”

“…Previous experiments from our laboratories have demonstrated that a continuous subcutaneous dose of 1 mg/kg/day (delivered via a subcutaneous pump) activates PP2A/PR55, reduces h-tau, and does not have any overt toxic effects in rodents (Liu et al, 2016;Shultz et al, 2015c). Furthermore, similar doses and treatment durations have been well-tolerated in human clinical trials (i.e., up to 90 mg per day for adult patients; Corcoran et al, 2010a), and a continuous dose is necessary to maintain consistent bioavailability because sodium selenate has a short half-life in vivo (approximately 1.2e2.9 h; Corcoran et al, 2010a).…”

“…The proteins in samples were separated with SDS-polyacrylamide gel electrophoresis, and the bands of proteins were electro-blotted onto polyvinyl difluoride (PVDF) membranes. The phosphorylation of tau at Ser198 (pS198) and Ser262 (pS262) is commonly implicated in tauopathies and neurodegeneration (Augustinack et al, 2002;Gotz et al, 2010;Lauckner et al, 2003;Liu et al, 2016;Sengupta et al, 1998). Moreover, we have previously found increased expression of pS198 and pS262 after a severe TBI (Shultz et al, 2015c).…”

Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link?

“…63 In a murine model of Alzheimer disease, the reduction of pTau levels corresponded to decreased electroencephalographic seizures. 69 These results support pTau as a common component of neurodegenerative diseases, including acquired epilepsies. 69 These results support pTau as a common component of neurodegenerative diseases, including acquired epilepsies.…”

A universal automated tool for reliable detection of seizures in rodent models of acquired and genetic epilepsy

“…For the study of acquired epilepsy, the two most common used models are the post–status epilepticus (SE) model and the traumatic brain injury–induced posttraumatic epilepsy (PTE) models . Conversely, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and Wistar Albino Glaxo from Rijswijk (WAG/Rij) are the most widely used models to study genetic generalized epilepsy with absence seizures .…”