Daphne Joy Garcia Galan

Introduction: Traumatic brain injury (TBI) occurs after a high impact blow to the head. In 2018, there were approximately 3.5 million cases of TBI in the US alone¹. Post traumatic epilepsy is one of the most debilitating consequences of TBI, inducing an epileptic seizure within the first year, and a second one within the first two years post-impact². Epileptogenesis theory lies in the neuron proliferation in the dentate gyrus of the hippocampi. After injury, Mammalian Target of Rapamycin (mTOR) pathway is disease-modifying for epilepsy development by inducing neuroinflammation and neurogenesis³. Since the current treatment is mere managing of the seizures, a hypothesis for new treatment involves the inhibition of the mTOR. Methods: In the first paper, 6 to 8-week-old mice were subjected to contusion injury by controlled cortical injury. After that, they were administered a 3/mg/kg injection of rapamycin 25-30 min after CCI⁴. The second paper evaluated the effect of rapamycin and repressed NLRP3 on neurological deficits, neurological damage, inflammatory response and mitochondrial dysfunction post TBI in vivo and in vitro⁵. A third paper injected mice with a FeCL_2. The mice were observed by someone blinded to the protocol to see any seizures. The levels of mTOR and P70S6k were measured using western blotting and immunohistochemistry⁶. Results: The results support the hypothesis that mTOR inhibition reduces post-traumatic epileptogenesis after CCI.  Their findings also suggest that even though there is some involvement with mTOR and the inhibition of disease progression and it prevents the initiation of epileptogenesis⁴. In a second experiment, Rapamycin activated mitophagy combined with NLRP3 inflammasome resistance preferably attenuates neuroinflammation, mitochondrial damage, and cell pressure, and demonstrate a better neuroprotective effect post-TBI, compared to single treatment⁵. The results for the third experiment showed decreased levels of mTOR and P70S6k after being injected with Rapamycin⁶. Conclusions: The role of mTOR in modifying functional hippocampal circuit reorganization after focal TBI supported the conclusion that rapamycin suppressed epileptogenesis and neurogenesis. Acute intervention of rapamycin suppressed mTOR activity and diminished the extent of neuronal death. In conclusion, mTOR inhibition seems like a promising therapeutic venue in the inhibition of TBI induced neurogenesis and other negative consequences, thereby prevents and reduces the development of PTE.

1. Morganti-Kossmann M. The complexity of neuroinflammation consequent to traumatic brain injury: from research to potential treatments. Acta Neuropathologica. December 2018. doi:doi.org/10.1007/s00401-018-1944-6.
2. Reddy D.S. Clinical Pharmacology of Modern Antiepileptic Drugs. International Journal of Pharmaceutical Sciences and Nanotechnology. 2017;10(6):3875-3890.
3. Brady R.D., Casillas-Espinosa P.M., Agoston DV, Bertram E.H. Modelling traumatic brain injury and posttraumatic epilepsy in rodents. Neurobiology of Disease. August 2018. doi:https://doi.org/10.1016/j.nbd.2018.08.007
4. Butler, Corwin R., et al. “Effects of Rapamycin Treatment on Neurogenesis and Synaptic Reorganization in the Dentate Gyrus after Controlled Cortical Injury in Mice.” Frontiers in Systems Neuroscience, 27 Nov. 2015, doi:10.3389/fnsys.2015.00163.
5. Chen Y, Meng J, Xu Q. Rapamycin Improves the neuroprotection effect of inhibition of NLRP3 Inflammasome activation after TBI. Brain Research. 2019;1710. https://doi.org/10.1016/j.brainres.2019.01.005.
6. Wang F, Chen F, Wang G, et al. Rapamycin Provides Anti-Epileptogenic Effects in a Rat Model of Post-traumatic Epilepsy Via Deactivation of mTOR Signaling Pathway. Experimental and Therapeutic Medicine. March 2018:4763-4770. doi:10.3892/etm.2018.6004.