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Blood–brain barrier leakage after status epilepticus in rapamycin‐treated rats II : Potential mechanisms
Author(s) -
Vliet Erwin A.,
Otte Willem M.,
Wadman Wytse J.,
Aronica Eleonora,
Kooij Gijs,
Vries Helga E.,
Dijkhuizen Rick M.,
Gorter Jan A.
Publication year - 2016
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13245
Subject(s) - status epilepticus , blood–brain barrier , medicine , leakage (economics) , neuroscience , epilepsy , anesthesia , psychology , central nervous system , economics , macroeconomics
Summary 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 TNF α‐induced endothelial barrier breakdown. Significance 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.