Abstracts

Rationale: Epileptogenesis describes the neurobiological processes that convert a healthy brain into an epileptic brain. There are no treatments that have been established to mitigate epileptogenesis in clinical practice. Protein phosphatase 2A (PP2A) regulates signalling pathways in the brain, and down-regulation of PP2A activity increases phosphorylated tau (p-tau). To investigate the role of PP2A in epileptogenesis, and the effects of a specific PP2A activator - sodium selenate - we utilized three well-characterised rat models of epilepsy: electrical amygdala kindling, post-kainic acid status epilepticus (post-SE) and post-traumatic epilepsy (PTE).Methods: For amygdala kindling, rats were implanted with subcutaneous osmotic pumps that delivered selenate (1 mg/kg/day) or vehicle continuously for four weeks. Rats received 30 electrical stimulations over the final three weeks of treatment. For post-SE experiments, SE was induced by kainic acid injections. Rats were then implanted with subcutaneous osmotic pumps that continuously released selenate or vehicle for 8 weeks. After five weeks of treatment, rats underwent MRI followed by continuous video-EEG monitoring. Rats were then given a drug washout period and then underwent additional video-EEG monitoring. For PTE, rats randomly suffered sham surgery or lateral fluid percussion injury and saline vehicle or selenate treatment. After three-month recovery, all rats underwent video-EEG monitoring during and after the treatment.Results: PP2A activity and expression of the PR55 regulatory subunit B were significantly decreased, and phosphorylation of tau was increased, in all three models. Selenate treatment slowed the progression of epileptogenesis in three models (delayed kindling and reduced spontaneous seizures post-SE and PTE), reversed the biochemical abnormalities, and reduced hippocampal atrophy in the post-SE model. In post-SE and PTE model, this effect was sustained after drug washout, which indicated an anti-epileptogenic effect.Conclusions: Epileptogenesis is associated with down-regulation of PP2A activity and an increase in phosphorylated tau, and enhancing PP2A activity with selenate is a potential anti-epileptogenic therapy.