Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat

Purpose: The mammalian target of rapamycin (mTOR) pathway has been implicated in contributing to progressive epileptogenesis in models of chronic epilepsy. Conversely, seizures themselves may directly cause acute activation of the mTOR pathway. To isolate the direct effects of seizures on the mTOR pathway, the time course and mechanisms of mTOR activation were investigated with acute seizures induced by pentylenetetrazole (PTZ), which does not lead to chronic epilepsy. Methods: Western blot analysis was used to assay the phosphorylation of Akt and S6, as measures of activation of the phosphoinositide 3-kinase (PI3K)/Akt and mTOR pathways, respectively, at various time points after PTZ-induced seizures in rats. The ability of wortmannin, a PI3K inhibitor, to inhibit PTZ seizure-induced activation of the mTOR pathway was tested. Key Findings: PTZ-induced seizures produced an immediate, transient mTOR activation lasting several hours, but no later, more chronic activation over days to weeks. This acute stimulation of the mTOR pathway by PTZ-induced seizures was mediated by upstream PI3K/Akt pathway activation and was blocked by a PI3K inhibitor. Significance: Compared with models of chronic epilepsy that exhibit biphasic (acute and chronic) mTOR pathway activation, PTZ-induced seizures produce only acute, but not chronic, mTOR activation. These results in the PTZ seizure model highlight potential differences in the involvement of the mTOR pathway between self-limited seizures and progressive epileptogenesis. These findings also suggest a potential therapeutic role of PI3K inhibitors in epilepsy.