title: The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice.
abstract: OBJECTIVE
  The mammalian target of rapamycin (mTOR) pathway integrates signals from different nutrient sources, including amino acids and glucose. Compounds that inhibit mTOR kinase activity such as rapamycin and everolimus can suppress seizures in some chronic animal models and in patients with tuberous sclerosis. However, it is not known whether mTOR inhibitors exert acute anticonvulsant effects in addition to their longer term antiepileptogenic effects. To gain insights into how rapamycin suppresses seizures, we investigated the anticonvulsant activity of rapamycin using acute seizure tests in mice.
  
  
  METHODS
  Following intraperitoneal injection of rapamycin, normal four-week-old male NIH Swiss mice were evaluated for susceptibility to a battery of acute seizure tests similar to those currently used to screen potential therapeutics by the US NIH Anticonvulsant Screening Program. To assess the short term effects of rapamycin, mice were seizure tested in ≤ 6 hours of a single dose of rapamycin, and for longer term effects of rapamycin, mice were tested after 3 or more daily doses of rapamycin.
  
  
  RESULTS
  The only seizure test where short-term rapamycin treatment protected mice was against tonic hindlimb extension in the MES threshold test, though this protection waned with longer rapamycin treatment. Longer term rapamycin treatment protected against kainic acid-induced seizure activity, but only at late times after seizure onset. Rapamycin was not protective in the 6 Hz or PTZ seizure tests after short or longer rapamycin treatment times. In contrast to other metabolism-based therapies that protect in acute seizure tests, rapamycin has limited acute anticonvulsant effects in normal mice.
  
  
  CONCLUSIONS
  The efficacy of rapamycin as an acute anticonvulsant agent may be limited. Furthermore, the combined pattern of acute seizure test results places rapamycin in a third category distinct from both fasting and the ketogenic diet, and which is more similar to drugs acting on sodium channels.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. Ahartma2@jhmi.edu
authors.forename: Adam L
authors.initials: AL
authors.lastname: Hartman
authors.forename: Polan
authors.initials: P
authors.lastname: Santos
authors.forename: Alison
authors.initials: A
authors.lastname: Dolce
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000208:Acute Disease; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007608:Kainic Acid; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole; D010766:Phosphorylation / Q000187:drug effects; D038601:Ribosomal Protein S6 / Q000378:metabolism; D012640:Seizures / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D001786:Blood Glucose; D007166:Immunosuppressive Agents; D038601:Ribosomal Protein S6; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D007608:Kainic Acid; D020155:3-Hydroxybutyric Acid; D020123:Sirolimus; D010433:Pentylenetetrazole