Mesial Temporal Lobe Epilepsy (MTLE) is a progressive neurological disorder and the most frequent type of epilepsy in adults. MTLE is often preceded by an initial insult that after a latent period leads to recurrent seizures. The main aim is to characterize mechanisms of seizure progression in epilepsy. Recent studies indicate that the blood-brain barrier (BBB; a defense mechanism that protects the brain against blood components) may be a new target. BBB leakage has been shown in epileptic humans and animals and is associated with epileptic activity and inflammation. I recently showed that artificial opening of the BBB increased seizure frequency, which is a major break-through in the epilepsy field.
However, the precise factors that contribute to progression of epilepsy are not known. It is also not known whether restoration of the BBB could lead to a milder form of epilepsy or even prevent the development of epilepsy. Therefore I want to start an innovative research line and focus on the role of a compromised BBB in the progression of epilepsy using a multidisciplinary approach in a rat model for MTLE. First, I will study whether the extent of BBB disruption during the early epileptogenic phase is predictive of seizure outcome in the chronic epileptic phase using Magnetic Resonance Imaging (MRI) in rats. Since BBB disruption leads to intrusion of (white) blood cells and plasma derived substances I will also use cellular imaging techniques (MR, confocal and voltage sensitive dye imaging) to determine the effects of these compounds on neuronal and glial network dynamics and on seizure progression. Finally, I will study whether anti-inflammatory therapies that restored BBB function in multiple sclerosis have disease modifying therapeutic effects in epilepsy.
Mesial Temporal Lobe Epilepsy is a severe form of epilepsy in adults that often cannot be controlled with antiepileptic drugs. Considering the fact that epilepsy is one of the most common neurological disorders, pharmacoresistance is a major health issue. Insights into the mechanisms that are involved in pharmacoresistance may ultimately lead to a therapy for pharmacoresistant epilepsy patients. The aim of the research described in my thesis is to investigate the role of the blood-brain barrier and multidrug transporters in pharmacoresistant epilepsy, using a rat model for temporal lobe epilepsy. My thesis provides evidence that multidrug transporters play an important role in pharmacoresistance by reducing antiepileptic drug levels in specific brain regions and shows that seizures can be controlled by pharmacological inhibition of multidrug transporters.
Rat brain bloodvessel stained for the multidrug transporter MRP2 (green) surrounded by glial endfeet processes (red).
Alternatively, an anti-epileptic drug that is not transported by multidrug
transporters (levetiracetam) also initially controlled seizures. However, the effects of both
these therapeutic approaches were transient.
The development of tolerance indicates that, in addition to overexpression of multidrug
transporters, other mechanisms of pharmacoresistance are relevant. Future research should
therefore not be limited to multidrug transporters but should also include anti-epileptic
drug properties and their targets.
Prof Jaap Troost presenting the 2010 Meinardi Prize to Erwin van Vliet
Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy
E.A van Vliet, S. da Costa Araújo, S. Redeker, E. Aronica and J.A. Gorter
Brain 2007; 130 (pt2):521-34.
PDF
Complexities in the association of human blood brain barrier disruption with seizures :
Importance of patient population and method of disruption.
E.A. van Vliet, J.A. Gorter. Brain 2007; 130: e78.
PDF
Region specific overexpression of P-glycoprotein at the blood-brain
barrier affects brain uptake of phenytoin in epileptic rats.
E.A van Vliet, R. van Schaik, P.M. Edelbroek, R.A. Voskuyl, S. Redeker,
E. Aronica, W.J. Wadman, J.A. Gorter.
JPET 2007; 322 (1), 141-7.
PDF
Inhibition of the multidrug transporter P-glycoprotein improves seizure
control in phenytoin-treated epileptic rats.
E.A van Vliet, R. van Schaik, P.M. Edelbroek, S. Redeker, E. Aronica,
W.J. Wadman, N. Marchi, A. Vezzani and J.A. Gorter.
Epilepsia 2006, 47(4):672-80.
PDF
Potential New Antiepileptogenic Targets Indicated by Microarray Analysis
in a Rat Model for Temporal Lobe Epilepsy.
J. A. Gorter, E. A. van Vliet, E. Aronica, T. Breit, H. Rauwerda, F. H. Lopes da Silva and W. J. Wadman.
J Neurosci 2006, 26(43):11083-11110.
PDF
COX-2 inhibition controls P-glycoprotein expression and promotes brain
delivery of the anti-epileptic drug phenytoin in chronic epileptic rats.
E.A. van Vliet, G. Zibell, A. Pekcec, J. Schlichtiger, P.M. Edelbroek,
L. Holtman, E. Aronica, J.A.Gorter, H. Potschka.
Neuropharmacology 2010, 58(2):404-12.
PDF
Een experimenteel diermodel voor temoraalkwab epilepsie: neuropathologie en aanvalspatronen. J.A. Gorter, E.A. van Vliet, E. Aronica, F.H. Lopes da Silva. Nederlands Tijdschrift voor Epileptologie 2000,28(1):17-22.
Upregulation of metabotropic glutamate receptor subtype mGluR2/3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eleonora Aronica, Erwin A. van Vliet, Oleg, A Mayboroda, Dirk Troost, Fernando H. Lopes da Silva, Jan A. Gorter. Eur J Neurosci 2000,12(7):2333-44.
Progression of spontaneous seizures after status epilepticus is associated with extensive bilateral loss of hilar parvalbumin and somatostatin immunoreactive neurons. J.A. Gorter, E.A. van Vliet, E. Aronica, F.H. Lopes da Silva. Eur J Neurosci 2001,13(4): 657-69.
Induction of neonatal sodium channel II and III a-isoform mRNAs in neurons and microglia after status epilepticus in the rat hippocampus. Eur J Neurosci 2001,13(6):1261-66.
Sodium currents in isolated rat CA1 pyramidal and dentate granule neurons in the post-status epilepticus model of epilepsy. S.O.M. Ketelaars, J.A. Gorter, E.A. van Vliet, F.H. Lopes da Silva, W.J. Wadman. Neuroscience 2001,105(1):109-20.
Expression of Id proteins increases in astrocytes in the hippocampus of epileptic rats. Eleonora Aronica, Dimitri Vandeputte, Erwin A. van Vliet, Fernando H. Lopes da Silva, Dirk Troost, Jan A. Gorter. Neuroreport 2001,12(11):2461-66.
Altered hippocampal gene expression prior to the onset of spontaneous seizures in the rat post status epilepticus model. Erik Hendriksen, Nicole A. Datson, Wim E.J.M. Ghijsen, Erwin A. van Vliet , Fernando H. Lopes da Silva, Jan Gorter, Erno Vreugdenhil. Eur J Neursci 2001, 14(9):1475-84.
Cystatin C, a cysteine protease inhibitor is persistently upregulated in neurons and glia in a rat model for mesial temporal lobe epilepsy. E. Aronica, E.A. van Vliet, E. Hendriksen, D. Troost, F.H. Lopes Da Silva, J.A. Gorter. Eur J Neursci 2001, 14(9):1485-91.
Glutamate transporters alterations in the reorganizing dentate gyrus are associated with progressive seizure activity in chronic epileptic rats. J.A. Gorter, E.A. van Vliet, E.A. Proper, P.E. de Graan, W.E.J.M. Ghijsen, F.H. Lopes da Silva, E. Aronica.J Comp Neurol 2002, 442:365-77.
Long-lasting increased excitability differs in dentate gyrus versus CA1 in freely moving chronic epileptic rats after electrically induced status epilepticus. J.A. Gorter, E.A. van Vliet, E. Aronica, F.H. Lopes Da Silva. Hippocampus 2002, 12:311-423.
Sodium Channel ß1-subunit expression is increased in reactive astrocytes in a rat model for mesial temporal lobe epilepsy. J.A. Gorter, E.A. van Vliet, F.H. Lopes da Silva, L.L. Isom, E. Aronica. Eur J Neurosci 2002, Eur J Neurosci 2002, 16:360-64.
Differential and long-lasting alterations of high voltage-activated calcium currents in CA1 and dentate granule neurons after status epilepticus. Jan A. Gorter, Aren J. Borgdorff, Erwin A. van Vliet, Fernando H. Lopes da Silva, Wytse J. Wadman. Eur J Neurosci 2002, 16(4):701-12.
Neuronal Cell Death in a Rat Model for Mesial Temporal Lobe Epilepsy is Induced by the Initial Status Epilepticus and not by Later Repeated Spontaneous Seizures. Gorter JA, Gonçalves Pereira PM, van Vliet EA, Aronica E, Lopes da Silva FH, Lucassen PJ. 2003. Epilepsia 44(5):647-58.
GAP-43 mRNA and protein expression in the hippocampal and parahippocampal region during the course of epileptogenesis in rats. Tolner, E. A., van Vliet, E. A., Holtmaat, A. J., Aronica, E., Witter, M. P., da Silva, F. H., Gorter, J. A. Eur J Neurosci 2003, 17(11): 2369-80.
Overexpression of the human major vault protein in gangliogliomas. E. Aronica, J. A. Gorter E.A. van Vliet, W.G.M.Spliet, C. W. M. van Veelen, Peter. C. van Rijen , S. Leenstra, M. Ramkema, G. L. Scheffer, R. J. Scheper, S.M. Sisodiya, D. Troost. Epilepsia 2003, 44(9):1166-75.
Progression of temporal lobe epilepsy in the rat is associated with immunocytochemical changes in inhibitory interneurons in specific regions of the hippocampal formation. E.A. van Vliet, E. Aronica, F.H. Lopes Da Silva, J.A. Gorter. Exp Neurol 2004, 187:367-79.
Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with Mesial Temporal Lobe Epilepsy. Eleonora Aronica, Jan A. Gorter, Marja Ramkema, Sandra Redeker, Filiz Ozbas-Gercerer, Erwin A. van Vliet, George L. Scheffer, Rik J. Scheper, Paul van der Valk, Johannes C. Baayen, Dirk Troost Epilepsia 2004, 45(5):441- 51.
Reorganisatie in de entorhinale schors van chronisch epileptische ratten. E. Tolner, F. Kloosterman, E.A. van Vliet, F.H. Lopes da Silva, J.A. Gorter. Epilepsie-Periodiek voor professionals 2004, 3(2):9-11.
Selective and persistent upregulation of mdr1b mRNA and P-glycoprotein in the parahippocampal cortex of chronic epileptic rats. E.A. van Vliet, E. Aronica, S. Redeker, N. Marchi, M. Rizzi, A. Vezzani, J.A. Gorter. Epilepsy Res 2004, 60(2-3):203-13.
Expression and cellular distribution of major vault protein, a putative marker for pharmacoresistance, in a rat model for temporal lobe epilepsy. E.A. van Vliet, E. Aronica, S. Redeker , J.A. Gorter. Epilepsia 2004, 45(12):1506-16.
Localisation of breast cancer resistance protein (BCRP) in micro-vessel endothelium of human control and epileptic brain. E. Aronica, J. A. Gorter , S. Redeker, E.A van Vliet, M. Ramkema, G.L. Scheffer, R.J. Scheper, P. van der Valk, S. Leenstra, J.C. Baayen, G.M.Spliet, D. Troost. Epilepsia 2005, 46(6):849-57.
Expression of multidrug transporters MRP1, MRP2 and BCRP shortly after status epilepticus, during the latent period and in chronic epileptic rats. E. A. van Vliet, S. Redeker, E. Aronica, P.M. Edelbroek, J.A. Gorter. Epilepsia 2005, 46(10):1569-80.
Increased expression of Ferritin, an iron storage protein in specific regions of the parahippocampal cortex of epileptic rats. J.A. Gorter, A.R.M. Mesquita, E.A. van Vliet, F.H. Lopes da Silva, E. Aronica. Epilepsia 2005, 46(9):1371-79.
Presubiculum stimulation in vivo evokes distinct oscillations in superficial and deep entorhinal cortex layers in chronic epileptic rats. E.A. Tolner, F. Kloosterman, E.A. van Vliet, M.P. Witter, F.H. Lopes da Silva, J.A. Gorter. J Neurosci 2005, 25(38):8755-65.
Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated epileptic rats, E.A van Vliet, R. van Schaik, P.M. Edelbroek, S. Redeker, E. Aronica, W.J. Wadman, N. Marchi, A. Vezzani and J.A. Gorter. Epilepsia 2006, 47(4):672-80.
Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy. J. A. Gorter, E. A. van Vliet, E. Aronica, T. Breit, H. Rauwerda, F. H. Lopes da Silva and W. J. Wadman. J Neurosci 2006, 26(43):11083-11110.
De rol van multidrug transporters in farmacoresistente epilepsie. E.A. van Vliet and J.A. Gorter. Epilepsie, periodiek voor professionals 2006, 4(4):10-12.
Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. E.A van Vliet, S. da Costa Araújo, S. Redeker, E. Aronica and J.A. Gorter. Brain 2007; 130 (pt2):521-34.
Region specific overexpression of P-glycoprotein at the blood-brain barrier affects brain uptake of phenytoin in epileptic rats. E.A van Vliet, R. van Schaik, P.M. Edelbroek, R.A. Voskuyl, S. Redeker, E. Aronica, W.J. Wadman and J.A. Gorter. JPET 2007; 322 (1), 141-7.
Complement activation in experimental and human temporal lobe epilepsy. E. Aronica, K. Boer, E.A. van Vliet, S. Redeker, J.C. Baayen, W.G.M. Spliet, P.C. van Rijen, D. Troost, F.H. Lopes da Silva, W.J. Wadman, J.A. Gorter. Neurobiol Dis, 2007; 26 (3): 497-511.
Complexities in the association of human blood brain barrier disruption with seizures: Importance of patient population and method of disruption. E.A. van Vliet, J.A. Gorter. Brain 2007; 130: e78.
Dynamic changes of proteases and protease inhibitors revealed by microarray analysis in CA3 and entorhinal cortex during epileptogenesis in the rat. J.A. Gorter, E.A. van Vliet, H. Rauwerda, T. Breit, R. Stad, R. van Schaik, E. Vreugdenhil, S. Redeker, E. Hendriksen, E. Aronica, F.H. Lopes da Silva, W.J. Wadman. Epilepsia 2007;48(s5): 53-64.
Therapieresistentie: te strenge controle bij Checkpoint Charley? E.A. van Vliet. Episcoop 2007; 3: 22-24.
Development of tolerance to levetiracetam in rats with chronic epilepsy. E.A. van Vliet, R. van Schaik, P.M. Edelbroek, F.H. Lopes da Silva, W.J. Wadman, J.A. Gorter. Epilepsia 2008;49(7):1151-9.
Decreased expression of synaptic vesicle protein 2A, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy. E.A. van Vliet, E. Aronica, S. Redeker, K. Boer, J.A.Gorter. Epilepsia 2009;50(3):422-33.
Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. L. Holtman, E.A. van Vliet, R. van Schaik, C.M. Queiroz, E. Aronica, J.A. Gorter. Ep Res 2009;84:56-66.
Targeting prostaglandin E2 EP1 receptors prevents seizure-associated p-glycoprotein up-regulation. A. Pekcec, B. Unkruer, J. Schlichtiger, J. Soerensen, A.M.S. Hartz, B. Bauer, E.A. van Vliet, J.A. Gorter, H. Potschka. JPET 2009; 330:939-947.
Farmacoresistente epilepsie: mogelijke oorzaken. Epilepsie, periodiek voor professionals 2009, 3(7):27-29.
Improved seizure control by alternating therapy of levetiracetam and valproate in epileptic rats. E.A. van Vliet, P.M. Edelbroek, J.A. Gorter. Epilepsia 2010, 51(3):362-70.
COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of the anti-epileptic drug phenytoin in chronic epileptic rats. E.A. van Vliet, G. Zibell, A. Pekcec, J. Schlichtiger, P.M. Edelbroek, L. Holtman, E. Aronica, J.A.Gorter, H. Potschka. Neuropharmacology 2010, 58(2):404-12. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. E. Aronica, K. Fluiter, A. Iyer, E. Zurolo, J. Vreijling, E.A. van Vliet, J.C. Baayen, J.A. Gorter. Eur J Neurosci 2010, 31(6):1098-9.
Erwin van Vliet was born on August 7, 1975 in Gouda, The Netherlands. After finishing his high school in 1992 he started his study “Biological and Medical Laboratory Research” at the Rotterdam University. After obtaining his Bachelor degree in 1997, he started as a research technician at the Institute for
Neurobiology of the University of Amsterdam, supervised by Prof. Dr. F.H. Lopes da Silva.
In 2000, he received a position as research technician at the Swammerdam Institute for Life Sciences of the Univerisity of Amsterdam. His project was entitled “anatomical and functional characteristics of synaptic reorganization in the (para)hippocampal area in a rat model for mesial temporal lobe epilepsy”, and he was supervised by Dr. J.A. Gorter. This project ended in 2003. Since he was fascinated by research, he applied for a personal grant as PhD-student at the Epilepsy Institute of The Netherlands and was awarded with a pre-clinical research fellowship in 2003.
In 2006 he received a Young Investigator Award (7th European Congress on Epileptology, Helsinki, Finland).
On November 16, 2007 he defended his thesis entitled
The role of the blood-brain barrier in pharmacoresistant epilepsy
and obtained his PhD degree at the University of Amsterdam (promotor Prof. dr. W.J. Wadman,
co-promotor dr. J.A. Gorter).
He worked as an epilepsy researcher at the Epilepsy Institute in The Netherlands Foundation, Heemstede (SEIN). In 2009 he was awarded with a VENI-grant from The Netherlands Organisation for Scientic Research (NWO). In 2010 he received the Harry Meinardi thesis prize for the best thesis on epilepsy 2007-2010.
This page was last updated on 5 nov 2010
