title: Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: Magnetic resonance imaging.
abstract: OBJECTIVE
  The mammalian target of rapamycin (mTOR) pathway has received increasing attention as a potential antiepileptogenic target. Treatment with the mTOR inhibitor rapamycin after status epilepticus reduces the development of epilepsy in a rat model. To study whether rapamycin mediates this effect via restoration of blood-brain barrier (BBB) dysfunction, contrast-enhanced magnetic resonance imaging (CE-MRI) was used to determine BBB permeability throughout epileptogenesis.
  
  
  METHODS
  Imaging was repeatedly performed until 6 weeks after kainic acid-induced status epilepticus in rapamycin (6 mg/kg for 6 weeks starting 4 h after SE) and vehicle-treated rats, using gadobutrol as contrast agent. Seizures were detected using video monitoring in the week following the last imaging session.
  
  
  RESULTS
  Gadobutrol leakage was widespread and extensive in both rapamycin and vehicle-treated epileptic rats during the acute phase, with the piriform cortex and amygdala as the most affected regions. Gadobutrol leakage was higher in rapamycin-treated rats 4 and 8 days after status epilepticus compared to vehicle-treated rats. However, during the chronic epileptic phase, gadobutrol leakage was lower in rapamycin-treated epileptic rats along with a decreased seizure frequency. This was confirmed by local fluorescein staining in the brains of the same rats. Total brain volume was reduced by this rapamycin treatment regimen.
  
  
  CONCLUSIONS
  The initial slow recovery of BBB function in rapamycin-treated epileptic rats indicates that rapamycin does not reduce seizure activity by a gradual recovery of BBB integrity. The reduced BBB leakage during the chronic phase, however, could contribute to the decreased seizure frequency in post-status epilepticus rats treated with rapamycin. Furthermore, the data show that CE-MRI (using step-down infusion with gadobutrol) can be used as biomarker for monitoring the effect of drug therapy in rats.
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Erwin A
authors.initials: EA
authors.lastname: van Vliet
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Willem M
authors.initials: WM
authors.lastname: Otte
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: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.|Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: Kooij
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Dijkhuizen
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: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004569:Electroencephalography; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005500:Follow-Up Studies; D007608:Kainic Acid / Q000633:toxicity; D008279:Magnetic Resonance Imaging; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000009:adverse effects* / Q000097:blood; D013226:Status Epilepticus / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D013459:Sulfur Hexafluoride / Q000378:metabolism; D013997:Time Factors; D014741:Video Recording
chemical_list: D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D010743:Phospholipids; C420843:contrast agent BR1; D007608:Kainic Acid; D020123:Sirolimus; D013459:Sulfur Hexafluoride
keywords: Blood-brain barrier; Contrast-enhanced magnetic resonance imaging; Epileptogenesis; Rapamycin; Status epilepticus; Temporal lobe epilepsy