OBJECTIVE Accumulating data have demonstra ted that seizures induced by kainate or pilocarpine activate the mammalian target of rapamycin (rmTOR) pathway and mTOR in hibitor rapamycin can inhibit rmTOR activation which subsequent ly has potential anti-epileptic effects.However, a preliminary study showed a paradoxical exacerbation of increased mTOR pathway activity reflected by S6 phosphorylation when rapamycin was administrated within a short period before kainate injection.In the present study, we examined this paradoxical effect of rapa mycin in more detail, both in normal rats and kainate-injected animals.METHODS The expression of mTOR signaling target both of phosphorylated and unphosphorylated forms were detected by Western Blotting analysis.Seizure onset and duration was mo nitored by Video.Neuronal cell death was detected by Fluoro Jade B staining.RESULTS In normal rats, we found that ra pamycin showed the expected dese-dependent inhibition of S6phesphoryhtion 3 ~24 h after injection, while a paradoxical ele vation of S6 phosphorylation was observed 1 h after rapamycin.Similarly, pretreatment with rapamycin over 10 h prior to kainate inhibits the kainate-induced mTOR activation.In contrast, rapa mycin administered 1-6 h before kainate causes a paradoxical increase in the kainate-induced mTOR activation.Rats pretrea ted with rapamycin 1 h prior to kainate showed an increase in se verity and duration of seizures and more neuronal cell death as compared to vehicle treated groups.In contrast, rapamycin pre treated 10 h prior to KA had no effect on the seizures and de creased neuronal cell death.The paradoxical effect of rapamycin on S6 phosphorylation was correlated with upstream mTOR signa ling and reversed by pre-treatment of perifosine, an akt inhibi tor.CONCLUSION These data indicate the complexity of S6regulation and its effect on epilepsy.Paradoxical effects of rapa mycin need to be considered in clinical applications, such as po tential treatments for epilepsy and other neurological disorders.