title: Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II: Potential mechanisms.
abstract: OBJECTIVE
  Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure activity during the chronic epileptic phase. Given rapamycin's role in growth and immune response, the potential therapeutic effects of rapamycin after status epilepticus with emphasis on brain inflammation and brain vasculature were investigated.
  
  
  METHODS
  Seven weeks after kainic acid-induced status epilepticus, rats were perfusion fixed and (immuno)histochemistry was performed using several glial and vascular markers. In addition, an in vitro model for the human BBB was used to determine the effects of rapamycin on transendothelial electrical resistance as a measure for BBB integrity.
  
  
  RESULTS
  (Immuno)histochemistry showed that local blood vessel density, activated microglia, and astrogliosis were reduced in rapamycin-treated rats compared to vehicle-treated rats. In vitro studies showed that rapamycin could attenuate TNFα-induced endothelial barrier breakdown.
  
  
  CONCLUSIONS
  These data suggest that rapamycin improves BBB function during the chronic epileptic phase by a reduction of local brain inflammation and blood vessel density that can contribute to a milder form of epilepsy.
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; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D017097:Electric Impedance; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005911:Gliosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007608:Kainic Acid / Q000633:toxicity; D037102:Lectins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000009:adverse effects*; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018690:Excitatory Amino Acid Agonists; D007166:Immunosuppressive Agents; D007608:Kainic Acid; D037102:Lectins; D020123:Sirolimus; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: Blood vessels; Blood-brain barrier; Inflammation; Rapamycin; Status epilepticus; Temporal lobe epilepsy