Abstracts

Rationale: Traumatic brain injury (TBI) is a major cause of disability and death. TBI is often accompanied by the subsequent development of posttraumatic epilepsy (PTE). Seizures of PTE are frequently intractable to available treatment options and attempts at preventing PTE have been unsuccessful. Understanding basic mechanisms of posttraumatic epileptogenesis is important for developing antiepileptogenic therapeutic approaches to PTE. The mammalian target of rapamycin (mTOR) pathway has been implicated in mediating mechanisms of epileptogenesis in other models of epilepsy and has also been reported to be activated in models of TBI. In this study, we tested the hypothesis that mTOR inhibition may have antiepileptogenic actions in the controlled cortical impact (CCI) model of experimental TBI. Methods: Adult male CD-1 mice received a craniotomy and a single episode of TBI to left lateral cortex using an electromagnetic CCI device with an injury depth of 2.0 mm. Control mice received sham surgery with a left craniotomy only. Rapamycin (6mg/kg/d, i.p.) or vehicle was initiated 1 hour after TBI and continued for 3 weeks. Western blot analysis of P-S6 expression in left hippocampus and neocortex was performed at various time points (1h, 3h, 6h, 24h, 3d, 1w, 2w, 3w) after TBI or sham surgery, and effects of rapamycin versus vehicle on P-S6 expression was also tested at 6h and 3d after TBI. Histological analysis of neuronal death by Fluoro-Jade B staining and mossy fiber sprouting by Timm s staining was performed at 3d and 1w, respectively, after sham surgery or TBI in vehicle- and rapamycin-treated mice. Video-EEG recordings monitored for seizures up to 16 weeks after TBI in vehicle- and rapamycin-treated mice. Results: mTOR pathway activation, as reflected by P-S6 expression, was significantly increased following TBI in both hippocampus and neocortex. This increase in P-S6 expression started at 3h, peaked at 6h and then decreased within 1w, returning to baseline by 2w after TBI. Rapamycin, administered after TBI, significantly blocked mTOR activation at 6h and 3d, and decreased neuronal death and mossy fiber sprouting in hippocampus. Initial video-EEG studies suggest that rapamycin decreases the development of spontaneous seizures during the first couple of months following TBI, although continued monitoring is ongoing to determine the long-term effects of rapamycin on PTE. Conclusions: The mTOR pathway is strongly activated following experimental TBI and may mediate mechanisms of epileptogenesis in the CCI model of TBI. The mTOR inhibitor rapamycin may have antiepileptogenic effects in this model. Supported by NIH NS056872.