Topiramate also has inhibitory effects on AMPA/kainite type ionotropic glutamate receptors and calcium channels and enhances GABAA receptor function. The action of lamotrigine on N-and P-type calcium channels, unlike phenytoin and topiramate, could potentially explain differences in 1418741-86-2 cost seizures profiles from rapamycin, although the mechanism of this effect remains unclear. The use of seizure-na?��ve, non-epileptic mice in this study allowed us to examine the short-term effects of rapamycin on nonpathological tissue. This is in contrast to long-term effects in disease models that may be dependent on a specific pathological context. The use of seizure-na?��ve, nonepileptic mice is a strategy that has successfully identified a wide variety of AZD-9291 anticonvulsants used in the clinic. Although potentially useful in further exploring the antiseizure mechanisms of rapamycin, the use of normal mice prevents us from drawing conclusions about the effects of rapamycin on mice with epilepsy. Similar to rapamycin, the high-fat, low-carbohydrate ketogenic diet suppresses mTOR activity. The ketogenic diet has been suggested to decrease mTOR activity via increased AMPK activity. If rapamycin and the ketogenic diet share similar metabolic effects and anticonvulsant mechanisms as suggested, then rapamycin treatment could be expected to protect against 6 Hzinduced acute seizures, similar to the ketogenic diet. We found no such protection in the rapamycin dosing regimens studied here. To put these new findings in perspective with our ketogenic diet results, there was,1 mA difference in the mean CC50 between rapamycin-and vehicle-treated mice, in contrast to the 2 mA difference in CC50 between the 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 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.
