title: Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats.
abstract: Inhibition of the mammalian target of rapamycin (mTOR) pathway has been suggested as a possible antiepileptogenic strategy in temporal lobe epilepsy (TLE). Here we aim to elucidate whether mTOR inhibition has antiepileptogenic and/or antiseizure effects using different treatment strategies in the electrogenic post-status epilepticus (SE) rat model.
  
  
  
  Effects of mTOR inhibitor rapamycin were tested using the following three treatment protocols: (1) "stop-treatment"-post-SE treatment (6 mg/kg/day) was discontinued after 3 weeks; rats were monitored for 5 more weeks thereafter, (2) "pretreatment"-rapamycin (3 mg/kg/day) was applied during 3 days preceding SE; and (3) "chronic phase-treatment"-5 days rapamycin treatment (3 mg/kg/day) in the chronic phase. We also tested curcumin, an alternative mTOR inhibitor with antiinflammatory and antioxidant effects, using chronic phase treatment. Seizures were continuously monitored using video-electroencephalography (EEG) recordings; mossy fiber sprouting, cell death, and inflammation were studied using immunohistochemistry. Blood was withdrawn regularly to assess rapamycin and curcumin levels with high performance liquid chromatography (HPLC).
  
  
  
  Stop-treatment led to a strong reduction of seizures during the 3-week treatment and a gradual reappearance of seizures during the following 5 weeks. Three days pretreatment did not prevent seizure development, whereas 5-day rapamycin treatment in the chronic phase reduced seizure frequency. Washout of rapamycin was slow and associated with a gradual reappearance of seizures. Rapamycin treatment (both 3 and 6 mg/kg) led to body growth reduction. Curcumin treatment did not reduce seizure frequency or lead to a decrease in body weight.
  
  
  
  The present study indicates that rapamycin cannot prevent epilepsy in the electrical stimulation post-SE rat model but has seizure-suppressing properties as long as rapamycin blood levels are sufficiently high. Oral curcumin treatment had no effect on chronic seizures, possibly because it did not reach the brain at adequate levels.
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Cato M
authors.initials: CM
authors.lastname: Drion
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lars E
authors.initials: LE
authors.lastname: Borm
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lieneke
authors.initials: L
authors.lastname: Kooijman
authors.affiliation: Department (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Epilepsy Institute in the Netherlands, Heemstede, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wytse J
authors.initials: WJ
authors.lastname: Wadman
authors.affiliation: Van't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Aloysius F
authors.initials: AF
authors.lastname: Hartog
authors.affiliation: Department (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Erwin A
authors.initials: EA
authors.lastname: van Vliet
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Gorter
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D003474:Curcumin / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004558:Electric Stimulation / Q000009:adverse effects*; D004569:Electroencephalography; D006624:Hippocampus / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000097:blood / Q000627:therapeutic use*; D013226:Status Epilepticus / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D003474:Curcumin; D020123:Sirolimus
keywords: Chronic seizures; EEG; Epileptogenesis; Temporal lobe epilepsy