title: Intermittent dosing of rapamycin maintains antiepileptogenic effects in a mouse model of tuberous sclerosis complex.
abstract: OBJECTIVE
  Inhibitors of the mechanistic target of rapamycin (mTOR) pathway have antiepileptogenic effects in preventing epilepsy and pathologic and molecular mechanisms of epileptogenesis in mouse models of tuberous sclerosis complex (TSC). However, long-term treatment with mTOR inhibitors may be required to maintain efficacy and potentially has chronic side effects, such as immunosuppression. Attempts to minimize drug exposure will facilitate translational efforts to develop mTOR inhibitors as antiepileptogenic agents for patients with TSC. In this study, we tested intermittent dosing paradigms of mTOR inhibitors for antiepileptogenic properties in a TSC mouse model.
  
  
  METHODS
  Western blot analysis of phosphorylation of S6 protein was used to assess the dose- and time-dependence of mTOR inhibition by rapamycin in control mice and conditional knockout mice with inactivation of the Tsc1 gene in glial fibrillary acidic protein (GFAP)-expressing cells (Tsc1(GFAP)CKO mice). Based on the Western blot studies, different dosing paradigms of rapamycin starting at postnatal day 21 were tested for their ability to prevent epilepsy or pathologic abnormalities in Tsc1(GFAP)CKO mice: 4 days of rapamycin only (4-∞), 4 days on-24 days off (4-24), and 4 days on-10 days off (4-10).
  
  
  RESULTS
  mTOR activity was inhibited by rapamycin in a dose-dependent fashion and recovered to baseline by about 10 days after the last rapamycin dose. The 4-10 and 4-24 dosing paradigms almost completely prevented epilepsy and the 4-10 paradigm inhibited glial proliferation and megalencephaly in Tsc1(GFAP)CKO mice.
  
  
  CONCLUSIONS
  Intermittent dosing of rapamycin, with drug holidays of more than 3 weeks, maintains significant antiepileptogenic properties in mouse models of TSC. These findings have important translational applications in developing mTOR inhibitors as antiepileptogenic agents in TSC patients by minimizing drug exposure and potential side effects.
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rensing
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
authors.forename: Lirong
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*
chemical_list: D000927:Anticonvulsants; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Epilepsy; Mechanistic target of rapamycin; Mice; Rapamycin; Seizure