Abstracts

Rationale: We recently found that the mammalian target of rapamycin (mTOR) signaling pathway is involved in epileptogenesis, and mTOR inhibitor rapamycin prevents epilepsy in a rat seizure model induced by kainate. However, rapamycin induces a paradoxical exacerbation of increased S6 phosphorylation when administrated within a short period before kainate injection. In the present study, we examined the effect of perifosine, an inhibitor of upstream target of mTOR, on epileptogenesis in kainate seizure model in rats.Methods: Six week old male Sprague-Dawley rats were pre-treated with vehicle or Perifosine (20 mg/kg/d, i.p.) for 3 days. On the fourth day, both groups received kainate (12 mg/kg, i.p.) to induce stage 4-5 seizures. Phosphorylation of Akt and S6 expression were assayed by Western blotting at different time intervals after kainate administration. Fluoro-Jade B staining was conducted to monitor neuronal cell death in hippocampus 7 days after kainate seizures. Timm staining was carried out 4 weeks after kainate injection to detect mossy fiber sprouting. To monitor spontaneous seizures, rats were implanted with neocortical electrodes and monitored for seizures by video-EEG for several weeks after kainate.Results: Perifosine administered for 3 days prior to kainate almost completely blocked kainate seizure-induced activation of Akt phosphorylation both acutely and chronically (p<0.01). However, Perifosine had slight inhibition effect on S6 phosphorylation. Interestingly, perifosine dramatically reduced kainate-induced neuronal cell death and mossy fiber sprouting (n = 5 rats/group). Video-EEG studies over a couple weeks suggested that perifosine reduced the development of spontaneous seizures, which showed better than, or at least the same effect as mTOR inhibitor rapamycin (n = 8-10 rats/group).Conclusions: Perifosine has potential anti-epileptogenic effects in the kainate rat epilepsy model. mTOR signaling pathway may be involved in epileptogenensis by alternative pathways besides typical Akt-mTOR-S6K-S6 pathway.