Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy

Neurobiol Dis. 2010 Oct;40(1):193-9. doi: 10.1016/j.nbd.2010.05.024. Epub 2010 May 26.

Abstract

Inhibition of mTOR by rapamycin has been shown to suppress seizures in TSC/PTEN genetic models. Rapamycin, when applied immediately before or after a neurological insult, also prevents the development of spontaneous recurrent seizures (epileptogenesis) in an acquired model. In the present study, we examined the mTOR pathway in rats that had already developed chronic spontaneous seizures in a pilocarpine model. We found that mTOR is aberrantly activated in brain tissues from rats with chronic seizures. Furthermore, inhibition of mTOR by rapamycin treatment significantly reduces seizure activity. Finally, mTOR inhibition also significantly suppresses mossy fiber sprouting. Our findings suggest the possibility for a much broader window for intervention for some acquired epilepsies by targeting the mTOR pathway.

Publication types

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

MeSH terms

  • Animals
  • Convulsants / pharmacology
  • Disease Models, Animal
  • Epilepsy / drug therapy*
  • Epilepsy / metabolism*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Male
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / physiology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Pilocarpine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / chemically induced
  • Seizures / drug therapy
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • Convulsants
  • Pilocarpine
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Sirolimus