PMID- 22578218 OWN - NLM STAT- MEDLINE DCOM- 20120914 LR - 20211203 IS - 1528-1167 (Electronic) IS - 0013-9580 (Print) IS - 0013-9580 (Linking) VI - 53 IP - 7 DP - 2012 Jul TI - Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. PG - 1119-30 LID - 10.1111/j.1528-1167.2012.03506.x [doi] AB - 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. CI - Wiley Periodicals, Inc. (c) 2012 International League Against Epilepsy. FAU - Galanopoulou, Aristea S AU - Galanopoulou AS AD - Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Laboratory of Developmental Epilepsy, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine, Bronx, New York, USA. aristea.galanopoulou@einstein.yu.edu FAU - Gorter, Jan A AU - Gorter JA FAU - Cepeda, Carlos AU - Cepeda C LA - eng GR - R01 NS020253-24/NS/NINDS NIH HHS/United States GR - R01 NS020253/NS/NINDS NIH HHS/United States GR - NS 38992/NS/NINDS NIH HHS/United States GR - R01 NS038992-10/NS/NINDS NIH HHS/United States GR - K02 NS062947/NS/NINDS NIH HHS/United States GR - NS62947/NS/NINDS NIH HHS/United States GR - R01 NS038992/NS/NINDS NIH HHS/United States GR - NS20253/NS/NINDS NIH HHS/United States GR - K02 NS062947-03/NS/NINDS NIH HHS/United States GR - R56 NS020253/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20120511 PL - United States TA - Epilepsia JT - Epilepsia JID - 2983306R RN - 0 (Anticonvulsants) RN - 0 (CD11b Antigen) RN - 0 (Calcium-Binding Proteins) RN - 0 (Enzyme Inhibitors) RN - 0 (TESC protein, human) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Anticonvulsants/*therapeutic use MH - CD11b Antigen/metabolism MH - Calcium-Binding Proteins/metabolism MH - Disease Models, Animal MH - Enzyme Inhibitors/therapeutic use MH - Epilepsy/*drug therapy/etiology MH - Humans MH - Mice MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC3389589 MID - NIHMS366784 EDAT- 2012/05/15 06:00 MHDA- 2012/09/15 06:00 PMCR- 2013/07/01 CRDT- 2012/05/15 06:00 PHST- 2012/05/15 06:00 [entrez] PHST- 2012/05/15 06:00 [pubmed] PHST- 2012/09/15 06:00 [medline] PHST- 2013/07/01 00:00 [pmc-release] AID - 10.1111/j.1528-1167.2012.03506.x [doi] PST - ppublish SO - Epilepsia. 2012 Jul;53(7):1119-30. doi: 10.1111/j.1528-1167.2012.03506.x. Epub 2012 May 11.