Rapamycin- and vehicle-treated mice in contrast to the difference in CC50 between the MCE Company PI-103 ketogenic diet and normal diet. Thus, despite similar effects on mTOR inhibition, rapamycin and the ketogenic diet appear unlikely to stop acutely-induced seizures via the same mechanisms. With respect to recurrent seizures in chronic seizure models, rapamycin and a ketogenic diet both prevent seizures long after kainic LY3023414 biological activity acid-induced status epilepticus, but differ in their ability to prevent recurrent seizures after pilocarpineinduced status epilepticus. These differences do not rule out the possibility that rapamycin and the ketogenic diet share some long-term effects on recurrent seizures after status epilepticus. AMPK activity is sensitive to multiple metabolic signals that ultimately affect ATP levels and in turn, increased AMPK activity inhibits mTOR activity. Relevant to neuronal activity, AMPKmediated changes in long-term potentiation are mTOR-dependent. Differences in acute seizure test profiles between three different treatments that affect AMPK activity support the hypothesis that downstream effects of neuronal mTOR inhibition likely depend on additional factors specific to each intervention. Rapamycin is known to bind FKBP12 to specifically inhibit mTORC1activity. Evidence that rapamycin acts similarly in vivo is shown by the ability of rapamycin and its derivatives to decrease recurrent seizures in animals and patients where TORC1 activity is abnormally high. Thus, it generally is assumed that rapamycin exerts its antiseizure actions by decreasing TORC1 activity. Protection in drug-induced chronic seizure models raises the possibility that mTOR inhibitors reverse a seizureinduced increase in the mTOR pathway. Specifically, after kainic acid-induced status epilepticus, increases in mTOR activity are noted 1�C6 h after seizure onset, then decrease to baseline values, only to increase again 3 days after onset. Both of these increases are reversed by administration of rapamycin. However, the connection between mTOR activity and excessive neuronal activity during seizures is not clear. mTOR activity is required in dendrites for arbor and spine morphogenesis in some studies, raising the possibility that these changes in neuronal morphology may impact seizures and/o
