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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.
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In the citing paper
“In animal models of TLE, tau hyperphosphorylation is observed in relevant brain regions, including the amygdala, hippocampus, and cortex, following chemical and electrical amygdala kindling (Jones et al., 2012; Liu et al., 2016; Alves et al., 2019).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liu et al., 2016
In the citing paper
“The antiepileptic effects of sodium selenate persist following drug washout in animal TBI models (Liu et al., 2016), highlighting a potential disease-modifying effect of PP2A upregulation by sodium selenate during epileptogenesis when applied in early PTE disease stage.”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liu et al., 2016
In the citing paper
“However, long-lasting phosphatase downregulation ultimately occurs, as evidenced by decreased PP2A activity paired with increased p-tau levels observed in epileptogenic brain regions following post-kainic acid status epilepticus, amygdala kindling, and fluid percussion injury in rats (Liu et al., 2016).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liu et al., 2016
In the citing paper
“Sodium selenate is a specific agonist for PP2A expressing the regulatory B subunit, an essential subunit for tau dephosphorylation by PP2A (Jones et al., 2012; Liu et al., 2016), and shows promise as a potential antiepileptic treatment option.”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liu et al., 2016
In the citing paper
“Sodium selenate treatment attenuates seizure activity and tau hyperphosphorylation and accumulation following administration of pentylenetetrazol or kainic acid as well as in the TLE model of amygdala kindling and the fluid percussion injury model of PTE (Jones et al., 2012; Liu et al., 2016).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liu et al., 2016
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Metadata
- Authors
- Liu, S.-J., Zheng, P., Wright, D. K., Dezsi, G., Braine, E., Nguyen, T., Corcoran, N. M., Johnston, L. A., Hovens, C. M., Mayo, J. N., Hudson, M., Shultz, S. R., Jones, N. C., & O’Brien, T. J.
- Affiliations
- The Royal Melbourne Hospital (AU)
- The University of Melbourne (AU)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-06-11
- Volume
- 139
- Issue
- 7
- Pages
- 1919-1938
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2412978786
- Cited by
- 127
- References
- 57
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 13 · 2023: 14 · 2022: 12 · 2021: 18 · 2020: 11 · 2019: 20 · 2018: 11 · 2017: 11 · 2016: 1
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- sodium selenate, epileptogenesis, protein phosphatase 2A, tau hyperphosphorylation, acquired epilepsy, amygdala kindling, status epilepticus, post-traumatic epilepsy, limbic epilepsy, drug withdrawal
- MeSH terms
- Brain Injuries, Traumatic, Animals, Anticonvulsants, Brain, Disease Models, Animal, Electroencephalography, Epilepsy, Kainic Acid, Kindling, Neurologic, Magnetic Resonance Imaging, Male, Phosphorylation, tau Proteins, Rats, Wistar, Excitatory Amino Acid Agonists, Rats, Protein Phosphatase 2, Selenic Acid
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