OBJECTIVE 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 kainic acid (KA).However, rapamycin induced 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.Phosphory-lation 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 6 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.