Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury

PLoS One. 2013 May 14;8(5):e64078. doi: 10.1371/journal.pone.0064078. Print 2013.

Abstract

Posttraumatic epilepsy is a major source of disability following traumatic brain injury (TBI) and a common cause of medically-intractable epilepsy. Previous attempts to prevent the development of posttraumatic epilepsy with treatments administered immediately following TBI have failed. Recently, the mammalian target of rapamycin complex 1 (mTORC1) pathway has been implicated in mechanisms of epileptogenesis and the mTORC1 inhibitor, rapamycin, has been proposed to have antiepileptogenic effects in preventing some types of epilepsy. In this study, we have tested the hypothesis that rapamycin has antiepileptogenic actions in preventing the development of posttraumatic epilepsy in an animal model of TBI. A detailed characterization of posttraumatic epilepsy in the mouse controlled cortical impact model was first performed using continuous video-EEG monitoring for 16 weeks following TBI. Controlled cortical impact injury caused immediate hyperactivation of the mTORC1 pathway lasting at least one week, which was reversed by rapamycin treatment. Rapamycin decreased neuronal degeneration and mossy fiber sprouting, although the effect on mossy fiber sprouting was reversible after stopping rapamycin and did not directly correlate with inhibition of epileptogenesis. Most posttraumatic seizures occurred greater than 10 weeks after TBI, and rapamycin treatment for one month after TBI decreased the seizure frequency and rate of developing posttraumatic epilepsy during the entire 16 week monitoring session. These results suggest that rapamycin may represent a rational treatment for preventing posttraumatic epilepsy in patients with TBI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Electroencephalography
  • Epilepsy, Post-Traumatic / metabolism
  • Epilepsy, Post-Traumatic / pathology
  • Epilepsy, Post-Traumatic / prevention & control*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / pathology
  • Multiprotein Complexes / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors

Substances

  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus