Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies

Epilepsia. 2010 Jan;51(1):27-36. doi: 10.1111/j.1528-1167.2009.02341.x. Epub 2009 Oct 8.

Abstract

Most current treatments for epilepsy are symptomatic therapies that suppress seizures but do not affect the underlying course or prognosis of epilepsy. The need for disease-modifying or "antiepileptogenic" treatments for epilepsy is widely recognized, but no such preventive therapies have yet been established for clinical use. A rational strategy for preventing epilepsy is to target primary signaling pathways that initially trigger the numerous downstream mechanisms mediating epileptogenesis. The mammalian target of rapamycin (mTOR) pathway represents a logical candidate, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. The importance of the mTOR pathway in epileptogenesis is best illustrated by tuberous sclerosis complex (TSC), one of the most common genetic causes of epilepsy. In mouse models of TSC, mTOR inhibitors prevent the development of epilepsy and underlying brain abnormalities associated with epileptogenesis. Accumulating evidence suggests that mTOR also participates in epileptogenesis due to a variety of other causes, including focal cortical dysplasia and acquired brain injuries, such as in animal models following status epilepticus or traumatic brain injury. Therefore, mTOR inhibition may represent a potential antiepileptogenic therapy for diverse types of epilepsy, including both genetic and acquired epilepsies.

Publication types

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

MeSH terms

  • Animals
  • Anticonvulsants / therapeutic use*
  • Brain Injuries / physiopathology
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Epilepsy / drug therapy*
  • Epilepsy / physiopathology
  • Epilepsy / prevention & control*
  • Gene Expression Regulation / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Malformations of Cortical Development / physiopathology
  • Mice
  • Models, Genetic
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / physiology*
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Sirolimus / antagonists & inhibitors*
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis / drug therapy*
  • Tuberous Sclerosis / genetics
  • Tuberous Sclerosis / prevention & control

Substances

  • Anticonvulsants
  • Intracellular Signaling Peptides and Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Sirolimus