Abstracts

Rationale: Protein phosphatase-2A (PP-2A) is a multi-subunit enzyme serine/threonine phosphatase and downregulation of PP-2A that plays a prominent role in a variety of pathologies, from carcinogenesis to neurodegenerative disease. One role of PP-2A is to dephosphorylate tau. Hypophosphorylated tau has been implicated in the pathogenesis of acquired forms of epilepsy, and we therefore hypothesised that down regulation of PP-2A may play a role in epileptogenesis and represent a novel target for anti-epileptogenic therapies. Methods: We first investigated in the electrical amygdala kindled rat model of temporal lobe epilepsy (versus sham kindled rats) the level of activity of PP-2A in relevant brain regions, using a immunoprecipitation phosphatase assay kit, and using western blotting the expression levels of PP-2A subunit C (catalytic subunit), PP-2A subunit B (regulatory subunit, PR 55), total tau and phosphorylation of tau on Ser 198 and 262, residues that are dephosphated by PP-2A. Next we investigated the effect of enhancing PP-2A activity in-vivo, by chronically treating with sodium selenate, an activator of PP-2A, at 1 mg/kg/day for 28 days during the period of electrical amygdala kindling, compared with saline treatment. Results: We found that PP-2A activities and PP-2A B subunit (PR55) expression were significantly decreased in amygdala, hippocampus and cortex of amygdala kindling rats compared with the same brain sections of sham kindled rats. Phosphorylation of tau on Ser 198 and 262 were both increased in these regions, compared with the same brain sections of sham kindled rats, consistent with a decreased activity of PP-2A. Further rats chronically treated with the PP-2A activator, sodium selenate, had significantly slower progression of the behavioural class of seizures during kindling, and of the progression of the total and primary electrographic seizure durations, compared with those treated with saline. On molecular analysis the selenate treated kindled rats had significantly increased the PP-2A activities and PP-2A B subunit expression, and decreased phosphorylation of tau on Ser 198 and 262, in amygdala, hippocampus and cortex, compared with rats treated with saline during the period of kindling. Conclusions: These results indicated that amygdala kindling epileptogenesis is associated with a down-regulation of PP-2A activity, associated with decreased expression of the regulatory B subunit and an increase in tau phosphorylation, and that pharmacologically enhancing PP2A activity with sodium selenate is a potentially viable anti-epileptogenic therapeutic statergy.