Targeting hyperphosphorylated tau with sodium selenate suppresses seizures in rodent models.

Abstract

Tau hyperphosphorylation has been implicated in the pathogenesis of a variety of forms of human epilepsy. Here we investigated whether treatment with sodium selenate, a drug which reduces pathological hyperphosphorylated tau by enhancement of PP2A activity, would inhibit seizures in rodent models. In vitro, sodium selenate reduced tau phosphorylation in human neuroblastoma cells and reversed the increase in tau phosphorylation induced by the PP2A inhibitor, okadaic acid. Sodium selenate treatment was then tested against three different rodent seizure models. Firstly the propensity of 6-Hz electrical corneal stimulation to induce seizures in adult mice was assessed following acute treatment with different doses of sodium selenate. Secondly, the number of seizures induced by pentylenetetrazole (PTZ) was quantified in rats following chronic sodium selenate treatment via drinking water. Finally, amygdala kindled rats were chronically treated with sodium selenate in drinking water and the length and the severity of the seizures evoked by stimulation of the amygdala recorded. The results demonstrated a dose-dependent protection of sodium selenate against 6-Hz stimulation induced seizures, and significant reduction in the total number of seizures following PTZ injection. Amygdala kindled rats chronically treated with sodium selenate had significantly shorter seizure duration compared controls, with more pronounced effects observed as the duration of treatment increased. The results of this study indicate that targeting hyperphosphorylated tau by treatment with sodium selenate has anti-seizure effects in a broad range of rodent models, and may represent a novel approach to treatment of patients with epilepsy.

• Authors: Nigel C Jones, Thanh Nguyen, Niall M Corcoran, Dennis Velakoulis, Tracy Chen, Robert Grundy, Terence J O'Brien, Christopher M Hovens
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 45 Issue 3 Pg. 897-901 (Mar 2012) ISSN: 1095-953X [Electronic] United States
• PMID: 22182692 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Convulsants
• Enzyme Inhibitors
• Selenium Compounds
• tau Proteins
• Okadaic Acid
• Proline
• Leucine
• Selenic Acid
• Pentylenetetrazole

Topics

• Amygdala (drug effects, metabolism)
• Analysis of Variance
• Animals
• Antioxidants (therapeutic use)
• Cell Line, Tumor
• Convulsants (adverse effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Electric Stimulation (adverse effects)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Leucine (genetics)
• Male
• Mutation (genetics)
• Neuroblastoma
• Okadaic Acid (pharmacology)
• Pentylenetetrazole (adverse effects)
• Phosphorylation (drug effects)
• Proline (genetics)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Seizures (drug therapy, etiology)
• Selenic Acid
• Selenium Compounds (therapeutic use)
• Time Factors
• Transfection
• tau Proteins (genetics, metabolism)