Rapamycin also inhibits mossy fiber sprouting in a number of models of status epilepticus

Rapamycin also inhibits mossy fiber sprouting in a number of models of status epilepticus. However, the importance of inhibiting mossy fiber sprouting is unclear because rapamycin can prevent mossy fiber sprouting without protecting against seizures after pilocarpine-induced status epilepticus. Electrophysiologically, mTOR is necessary for long-term potentiation and long-term depression.The effect of rapamycin on synaptic transmission may be mediated via decreased neuronal excitability and/or neurotransmitter release. Whether these morphological and physiological effects are the specific mechanism of seizure protection is unclear. In summary, decreased rapamycin-related neuronal excitability in some paradigms may be the result of mTOR inhibition but these studies do not rule out the possibility of an off-target effect, particularly given the broad effects of mTOR activity on protein synthesis, lipid metabolism, and autophagy. The limited seizure protection after a 3 d rapamycin exposure in the seizure-nave mice studied here may be due to unintended deleterious effects of prolonged mTOR suppression, in contrast to physiological mTOR suppressors where mTOR activity eventually rebounds. Another potential explanation is that the 3 d rapamycin regimen used here may suppress activity of the other mTOR protein complex, TORC2, with a subsequent deleterious effect on Akt activity. Consistent with only transient protection in the MES-T test, there may be an optimal degree of timing or extent of mTOR suppression that confers seizure protection in preclinical tests, though it is conceivably difficult to pharmacologically purchase Flumatinib achieve such a balance. Daucosterol cost Finally, rapamycin is unlikely to have global antiseizure benefits, as it fails to protect in a model of infantile spasms induced by betamethasone and NMDA, even when administered before and after spasms started. Pretreatment or sustained exposure to rapamycin appears to be necessary to prevent seizures in preclinical models, as outlined previously. A requirement for prolonged rapamycin treatment is consistent with our finding that a 3-day treatment with rapamycin is more effective than a short 6 h treatment prior to kainic acid-induced seizures. Potentially more important than length of treatment, it appears that ra