Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target

Aristea S. Galanopoulou, Jan A. Gorter, Carlos Cepeda

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism. Loss-of-function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy, and neurodevelopmental disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes; mutations in phosphatase and tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations in the STE20-related kinase adaptor alpha (STRADalpha); and neurofibromatosis type 1 attributed to neurofibromin 1 mutations. Inhibition of the mTOR pathway with rapamycin may prevent epilepsy and improve the underlying pathology in mouse models with disrupted mTOR signaling, due to PTEN or TSC mutations. However the timing and duration of its administration appear critical in defining the seizure and pathology-related outcomes. Rapamycin application in human cortical slices from patients with cortical dysplasias reduces the 4-aminopyridine- induced oscillations. In the multiple-hit model of infantile spasms, pulse high-dose rapamycin administration can reduce the cortical overactivation of the mTOR pathway, suppresses spasms, and has disease-modifying effects by partially improving cognitive deficits. In post-status epilepticus models of temporal lobe epilepsy, rapamycin may ameliorate the development of epilepsy-related pathology and reduce the expression of spontaneous seizures, but its effects depend on the timing and duration of administration, and possibly the model used. The observed recurrence of seizures and epilepsy-related pathology after rapamycin discontinuation suggests the need for continuous administration to maintain the benefit. However, the use of pulse administration protocols may be useful in certain age-specific epilepsy syndromes, like infantile spasms, whereas repetitive-pulse rapamycin protocols may suffice to sustain a long-term benefit in genetic disorders of the mTOR pathway. In summary, mTOR dysregulation has been implicated in several genetic and acquired forms of epileptogenesis. The use of mTOR inhibitors can reverse some of these epileptogenic processes, although their effects depend upon the timing and dose of administration as well as the model used.

Original languageEnglish (US)
Pages (from-to)1119-1130
Number of pages12
JournalEpilepsia
Volume53
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Sirolimus
Epilepsy
Pharmaceutical Preparations
Mutation
Pathology
Infantile Spasms
Seizures
Phosphoric Monoester Hydrolases
Neurofibromin 1
Multiple Hamartoma Syndrome
Megalencephaly
Polyhydramnios
Malformations of Cortical Development
4-Aminopyridine
Inborn Genetic Diseases
Tuberous Sclerosis
Neurofibromatosis 1
Temporal Lobe Epilepsy
Status Epilepticus
Spasm

Keywords

  • Cortical dysplasia
  • Infantile spasms
  • Kainic acid
  • Pilocarpine
  • Status epilepticus
  • Tuberous sclerosis

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Finding a better drug for epilepsy : The mTOR pathway as an antiepileptogenic target. / Galanopoulou, Aristea S.; Gorter, Jan A.; Cepeda, Carlos.

In: Epilepsia, Vol. 53, No. 7, 07.2012, p. 1119-1130.

Research output: Contribution to journalArticle

Galanopoulou, Aristea S. ; Gorter, Jan A. ; Cepeda, Carlos. / Finding a better drug for epilepsy : The mTOR pathway as an antiepileptogenic target. In: Epilepsia. 2012 ; Vol. 53, No. 7. pp. 1119-1130.
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