The concept of the blood-brain barrier (termed hematoencephalic barrier) was first introduced by Lina Stern in 1921, although the early work by Paul Ehrlich and Edwin Goldmann suggested the compartmentalization between blood and brain and a role of blood vessels in maintaining these compartments (Ehrlich, 1885; Goldmann, 1913; Vein, 2008). However, actual proof of the existence of a BBB came in the 1960s. Since then, significant progress has been made in defining the functions and properties of that barrier.
The BBB is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules and cells into brain and preserves ionic homeostasis within the brain microenvironment (Pardridge, 2007; Rubin & Staddon, 1999; Ueno, 2007). Formed at the interface between blood and brain parenchyma, the BBB is composed of a tightly sealed monolayer of brain endothelial cells at the brain capillary surface and adjacent perivascular cells, including astrocytes and pericytes. Both astrocytic endfeet and pericyte processes wrap the abluminal capillary surface and through indirect or direct synapse-like “peg-socket” interactions provide physical support and stability to the BBB (Abbott, 2002; Armulik et al, 2010; Kim et al, 2006; Williams et al, 2001). In recent years, the concept of a BBB has been significantly extended to the concept of a neurovascular unit, which best describes the dynamic communication between brain endothelium, neurons, astrocytes, pericytes, vascular smooth muscle cells, microglia and perivascular macrophages at the interface between the blood and brain parenchyma compartments (Hawkins & Davis, 2005; Wolburg et al, 2009). A healthy brain relies on all of the cells of the neurovascular unit to function properly and communicate with each other in order for neuronal synapses and circuitries to maintain normal cognitive functions (Fig. 1).
2. Blood-brain barrier junctional complexes
The structural properties of the BBB are primarily determined by the endothelial junctional complexes, consisting of tight junctions (TJ) and adherens junctions (AdJ). The interactions between brain endothelial cells provide high endothelial electrical resistance barrier, in the range of 1500-2000 Ω.cm2 (pial vessels), as compared to 3-33 Ω.cm2 endothelial barrier in other tissues (Butt et al., 1990; Crone & Christensen, 1981). The TJ complexes seal the interendothelial cleft and regulates BBB paracellular permeability, while the AdJ is important for initiating and maintaining endothelial cell-cell contact (Denker &Nigam, 1998; Huber et al, 2001; Gonzalez-Mariscal et al, 2003). Structurally both complexes are composed of transmembrane proteins, which physically interact with their counterparts on the plasma membrane of adjacent cells, and cytoplasmic plaque proteins, which provide a link between transmembrane TJ/AdJ proteins and the actin cytoskeleton and participate in intracellular signaling (Fig. 2).
The TJ transmembrane proteins include occludin, claudins (for example, claudin-5, -3, -12, -1) and junctional adhesion molecule (JAM) -A, -B and -C (Martin-Padura et al, 1998; Mitic & Aderon, 1998; Staddon and Rubin, 1996). Occludin (MW ~65kDa) was one of the first TJ transmembrane proteins to be described. It has four transmembrane spanning regions, two extracellular loops responsible for intercellular adhesion and maintaining transendothelial electrical resistance, and N- and C- terminal sites through which occludin can fully oligomerize or directly interact with scaffolding TJ [zonula occludens -1, -2, -3 (ZO-1, -2- 3)] and regulatory proteins [protein kinase C (PKC), tyrosine kinase c-Yes and Phosphatidylinositol 3-kinases (PI3K)] (Clump et al, 2005; Feldman et al 2005; Suzuki et al, 2002). The C-terminus of occludin plays a critical role in paracellular channel formation, mediating endocytosis and trafficking of occludin (Li et al, 2005; Nusrat et al, 2005). It is also involved in the integration and function of occludin within the TJ complex.
Claudins (MW 20 to 27 kDa) are the principal barrier-forming proteins. They belong to the PMP22/EMP/MP20/claudin family of proteins (Koval, 2006). Until now, twenty different claudins have been discovered and each of them shows a unique pattern of tissue expression and interactions. Claudins have a similar structural pattern to occludin: four membrane-spanning regions, two extracellular loops and two cytoplasmic termini (Morita et al, 1999; Nitta et al, 2003; Ruffer & Gerke, 2004; Soma et al, 2004). The first extracellular loop influences paracellular charge selectivity, while the second loop is known as a receptor for a bacterial toxin. Similar to occludin, the C-terminal site of claudins possesses a binding site (domain) for cytoplasmic proteins (ZO-1, ZO-2, ZO-3, MUPP1, PATJ) through a PDZ motif (Koval, 2006; Morita et al, 1999; Ruffer & Gerke, 2004). The role of the N-terminal site is still unclear. Brain endothelial cells express the cell specific claudin-5, which plays pivotal role in interendothelial occlusion and size selective permeability (Nitta et al, 2003; Ohtsuki et al, 2007). Besides claudin-5, recent data suggest the BBB possesses claudin-3, mostly during vasculogenesis, claudin-1, during adult brain angiogenesis and barrier genesis, and claudin-12 (Belanger et al, 2007; Lampugnani et al, 2010). However, there is little information on the interaction between these claudins and their role at the BBB.
JAM-A, -B, and -C (MW 32 kDa) are members of the immunoglobulin superfamily of proteins (Martin-Padura et al 1998). Similar to other immunoglobulins, these molecules are composed of a single membrane spanning domain, an extracellular domain, and two termini, an extracellular N-terminus and a short cytoplasmic tail C-terminus (Sobocki et al, 2006; Williams et al, 1999). The extracellular region of JAMs consists of two IgG-like domains and it appears to be subject to glycosylation, although the function of that glycosylation is still unknown. The short cytoplasmatic tail (40 amino acids) contains a binding domain which facilitates interactions with TJ associated scaffold proteins such as ZO-1, AF-6, ASIP/Par3, and cingulin (Bazzoni et al 2000; Bazzoni & Dejana, 2004; Williams et al, 1999). It also has phosphorylation sites for PKC, PKA and casein kinase II (Williams et al, 1999). JAMs display different patterns of homophilic and heterophilic cis- and trans- interactions. While they interact with JAM on adjacent cells, they can also act as adhesion molecules for interacting with integrins on leukocytes to regulate leukocyte trafficking (Bazzoni et al, 2000; Lamagna et al, 2005).
The cytoplasmic plaque proteins of TJ are divided into PDZ containing proteins (family membrane-associated guanylate-kinase (MAGUK) homologues (ZO-1, ZO-2, ZO-3), partitioning-defective proteins Par-3, Par-6, afadin/Af-6) and PDZ lacking proteins (cingulin, 7H6, Rab13, ZONAB, AP-1, PKCζ, PKCλ, heterotrimeric G protein) (Gonzalez-Mariscal et al, 2000, 2003; Ponting et al, 1999). The PDZ containing TJ proteins act as scaffolds that bring together cytoskeleton, signaling and integral proteins at specific regions of the plasma membrane and, via the PDZ domain, have a critical role in clustering and anchoring transmembrane proteins (Fanning et al, 2007; Hamazaki et al, 2002; McNeil et al, 2006). For example, ZO-1 functions as a multidomain scaffold that coordinates assembly of transmembrane and cytosolic proteins, including components of the cortical cytoskeleton, into TJs and/or regulates the activity of these proteins once they are assembled. Thus, ZO-1 is required for the normal kinetics of TJ assembly, for TJ specific localization and unique organization of transmembrane proteins (Gonzalez-Mariscal et al, 2000; McNeil et al, 2006; Utepbergenov et al, 2006).
PDZ lacking proteins have a variety functions at the TJ complex. For example, cingulin acts as a cross-link between TJ proteins (ZO-2, ZO-3, AF-6, JAM) and the actin-myosin cytoskeleton. Rab proteins (Rab13, Rab3b) have a role in the docking and fusion of transport vesicles at the TJ complex, while PKCζ and PKCλ have roles in regulating polarization and in TJ assembly (Andreeva et al, 2006; Suzuki et al, 2002; Terai et al, 2006; Yamanaka et al, 2001;). G proteins (Gα-i0, Gα-i2, Gα12, Gαs) co-immunoprecipitate with ZO-1 and play a role in accelerating TJ assembly and maintaining transendothelial electrical resistance (Citi &Cordenonsi, 1998; Meyer et al, 2003).
The major AdJ transmembrane protein in endothelial cells is vascular endothelium (Ve)-cadherin. The AdJ cytoplasmic plaque proteins include catenin family members (α-, β-catenin, p120) (Bazzoni & Dejana, 2004; Nagafuchi, 2001). Ve-cadherin is an important determinant of microvascular integrity both
The actin cytoskeleton is also a critical component for establishing brain endothelial barrier integrity. The cytoskeleton is composed of three primary elements: actin microfilaments, intermediate filaments and microtubules. Actin microfilaments are focally linked to multiple membrane adhesive proteins such as cadherin, occludin, zonula occludens, catenins and focal adhesion complex, forming a structure known as the actin-rich adhesion belt and providing physical support to the junctional complexes (Lai et al, 2005; Small et al, 1999; Tao et al, 1996). In addition, actin microfilaments are involved in generating tension via myosin light chain phosphorylation and actin stress fiber formation during the unsealing of the junctional complex (Small et al, 1999; Stamatovic et al, 2003; Wang et al, 1983). A second major element of the cytoskeleton is the microtubules, polymers of α- and β-tubulins, which participate in rapid assembly of actin filaments and focal adhesion, isometric cellular contraction and/or increased transendothelial leucocyte migration (Honore et al, 2005; Tzima, 2006). A third major element of the cytoskeletal machinery is the intermediate filaments (predominantly vimentin) which have a role in reorganization of actin filaments and microtubules (Dudek& Garcia, 2001).
3. Blood-brain barrier transport systems
3.1. Transcellular transport
Due to the restrictive angioarchitecture of the BBB, brain endothelial cells have developed specific transport systems which allow the controlled exchange of proteins, nutrients and waste products between blood and brain. In this way, while impeding the general influx of hydrophilic intravascular substances from blood to brain, carrier- and receptor-mediated transport systems promote the transport into brain of select compounds important for cerebral function. In addition, active efflux transport systems promote the clearance of select compounds (e.g. waste products) from brain to blood. There is some ‘non-selective’ transport of compounds across the BBB through nonspecific vesicular transport (fluid phase endocytosis or adsorptive endocytosis) (Lossinsky et al, 1983; Lossinsky & Shivers, 2004).
Fluid phase endocytosis, adsorptive endocytosis and caveolae are some of the systems involved in the transcytosis of compounds across the brain endothelium. Transcytosis describes the vectorial movement of molecules within endocytotic vesicles across the cerebral endothelium (primarily from the luminal cell side to the abluminal side) where exocytosis occurs (Lossinsky & Shivers, 2004). Brain capillary endothelial cells contain two kinds of vesicles that are open to the luminal blood capillary space: caveolae and clathrin-coated pits/vesicles. Clathrin is a self-assembling protein whose polymerization into a polyhedral network promotes membrane vesiculation and budding of selected receptors (Miwako et al, 2003; Mukherjee et al, 1997). Compared to peripheral endothelia, the brain capillary endothelium is particularly enriched in clathrin-coated pits/vesicles (Lossinsky & Shivers, 2004). These are predominantly expressed on the luminal side suggesting that clathrin-dependent transcytosis is primarily from blood to brain. Clathrin-coated pits recruit cell-surface receptors and then, through a series of highly regulated steps, pinch off to form clathrin-coated vesicles, which further may fuse with a transcytotic endosome (Miwako et al, 2003; Mukherjee et al, 1997).
Caveolae are bud-like invaginations formed by the concentration of the caveolin proteins. These vesicles are enriched in cholesterol and glycosphingolipids on cellular membranes as well as glycosyl phosphatidyl inositol (GPI)-anchored proteins, not present in the coated pits (Hommelgaard et al, 2005; Kirkham & Parton, 2005). Caveolae are found on both luminal and abluminal plasma membranes of cerebral endothelial cells indicating bidirectional transcytosis from blood to brain and from brain to blood (Lossinsky & Shivers, 2004). Caveolae contain an abundance of membrane receptors, transporters and signaling molecules, suggesting their involvement in various important cellular processes in addition to their role in the endocytosis/transcytosis. Recent findings regarding the process of endocytosis have pinpointed the merging endosomes for both types of endocytotic pathways (see for review Hommelgaard et al, 2005).
In fluid-phase transcytosis, invagination of caveolae entraps bulk plasma and soluble plasma molecules. The vesicles are then transported across the cerebral endothelium. In this transport process, there is a lack of interaction between the transported molecules and the caveolar vesicular membrane (Lossinsky & Shivers, 2004; Predescu et al, 2007). A very small portion fluid-phase transcytosis can occur via clathrin-coated pits/vesicles.
Adsorptive transcytosis can be
Non-specific adsorptive transcytosis does not involve specific plasma membrane receptors and endocytosis is initiated through charge-charge interaction between polycationic substances and negative charges on the endothelial surface. Molecules that penetrate the brain via this mechanism include, but are not limited to, various cationic proteins. Clathrin-coated pits along the luminal surface of ECs are negatively charged and thus capable of binding positively charged substances (Hervé et al, 2008; Villegas et al, 1993). A few studies have, however, demonstrated that caveolae are involved in adsorptive endocytosis by transferring of cationized
Brain uptake via non-specific and specific adsorptive transcytosis is time- and concentration-dependent, and requires energy. Uptake via these types of endocytosis is slow compared with carrier-mediated transport of nutrients (e.g. glucose), taking minutes to occur. Both non-specific and specific adsorptive endocytosis/transcystosis are also saturable processes with the main difference being that non-specific adsorptive transcytosis becomes saturated at higher concentrations (micromolar level) while specific adsorptive transcytosis becomes saturated at a low nanomolar range (Hervé et al, 2008).
3.2. Carrier mediated: blood-to-brain influx systems
BBB possesses a wide array of carrier-mediated transport systems for small molecules to support and protect CNS function. For example, the blood-to-brain influx transport systems supply nutrients, such as glucose and amino acids.
D-glucose in the primary energy source for the brain and the BBB has very high levels of the facilitative (Na+-independent) glucose transporter, GLUT1 (SLC2A1) which transports D- but not L-glucose (Cornford et al, 1993; Pardridge et al, 1990). GLUT1 is localized on both the luminal and abluminal sides of the BBB. As well as transporting D-glucose, GLUT1 transports hexoses and an oxidized form of L-ascorbic acid, L-dehydroascorbic acid. It is considered to have role in maintaining the high concentration of L-ascorbic acid in the brain compared with plasma (McAllister et al 2001; Vemula et al, 2009). In addition, GLUT1 can transport some glycosylated peptides (e.g. L-serinyl-β-D-glucoside analogues of Met5 enkephalin) (Masand et al, 2006).
Amino acids like L-tyrosine, L-tryptophan, and L-histidine are transported from the blood to the brain via a Na+-independent neutral amino acid transporter (system L) (Boado et al, 1999, Ohtsuki, 2004). This is a heteromeric transporter with a light chain (LAT1; SLC7A5) and a heavy chain (4F2hc; SLC3A2)(Omidi et al, 2008). As with GLUT1, it is facilitative and present on both the luminal and abluminal membranes. Same transporters is involved in transports L-leucine, L-isoleucine, L-valine, L-methionine, L-threonine, and L-phenylalanine (Audus & Borchardt, 1986; Omidi et al, 2008; Reichel et al, 1996; Xiang et al, 2003). Several amino acid-mimetic drugs, alkylating agent melphalan, the antiepileptic drug gabapentin, and the muscle relaxant baclofen use a System L for the influx form blood to brain (Luer et al, 1999; Sakaeda et al, 2000). Thus a high-protein diet reduces the concentration of these drugs in the brain due to competitive inhibition at the BBB.
The basic amino acids, such as L-lysine and l-arginine have a CAT1 (SCL7A2) transporter which expression is concentrated in brain capillaries (Lyck et al, 2009; Umeki et al, 2002). TAUT (SLC6A6) mediates taurine transport at the BBB, and due to neuroprotective effect of taurine the therapeutic manipulation of this transporter is important strategy in the treatment of neurodegenerative disorders (Kang et al, 2002; Lyck et al, 2009).
MCT1 (SCL16A1) mediates influx transport of monocarboxlic acids, such as lactate and pyruvate. MCT1 in the brain and the brain uptake rate of lactate are particularly increased during the suckling period allowing brain the use lactate from milk (Batrakova et al, 2004; Kido et al 2000; Umeki et al, 2002).
CNT1 (SCL28A1) mediates transport of nucleosides and their analogues while Oatp2 (SLCO1B1; SLC21A6) mediates transport of organic anions and opioids (Bourasset et al, 2003; Cansev, 2006; Gao et al, 2000; Li et al, 2001). Both of these blood-to-brain influx transport systems are candidates to enhance drug delivery to the brain.
Creatine is important in energy storage in the brain and it is uptaken via CRT [SLC6A8] transporter (Braissant et al, 2001; Ohtsuki et al, 2002; Tachikawa et al, 2009;). This transporter is expressed on both luminal and an abluminal membrane of brain capillary endothelial cells and for this transporter is documented to mediate creatine supply to the brain (Braissant et al, 2001; Ohtsuki et al, 2002). Due to the fact that creatine has a neuroprotective effect, targeting CRT at BBB is the strategy to increase brain creatine levels and to prevent neurodegeneration (Fig. 3).
3.3. BBB efflux transporters: brain-to-blood efflux system
The BBB is involved in the brain-to-blood efflux transport of hydrophilic small molecules generated in the brain, such as neurotransmitters, neuromodulators, end-metabolites of neurotransmitters, uremic toxins, and also peptides, such as immunoglobulins.
Brain endothelial cells contain the norepinephrine transporter (NET), localized at the abluminal membrane and serotonin transporter (SERT), localized at both the abluminal and luminal membrane. In this way the brain microvasculature could receive signals and be regulated by monoamines released from adrenergic and serotonergic neurons (Ohtsuki, 2004; Wakayama et al, 2002). The abluminally localized NET and SERT is thought to be an inactivation system for neurotransmitters around the brain capillaries. The presence of luminal SERT is thought to play a role in serotonin clearance from the intravascular space (mostly secreted by platelets) to maintain cerebral blood flow (Nakatani et al, 2008; Olivier et al, 2000). Besides monoamines, brain endothelial cells are also involved in the efflux transport of GABA via Betaine/GABA transporter-1 (BGT-1; SLC6A12) or murine GABA transporter 2 (GAT2) present on the abluminal membrane (Gibbs et al, 2004; Kakee et al, 2001; Takanaga et al, 2001).
Brain endothelial cells exhibit stereo-selective efflux transport of aspartic acid (Asp), via ASC transporter ASCT2, selectively transporting the L-isomer of Asp (Tetsuka et al, 2003). In addition, excitatory amino acid transporters, EAATs, have been detected on the abluminal membrane of brain endothelial cells having a role in transport of both L- and D- Asp isomers and L-glutamate (Ennis et al, 1998; O'Kane et al, 1999; Tetsuka et al, 2003). System A is a transport system (ATA1, ATA2, ATA3) for small neutral amino acids that accepts L-alanine, L-proline and glycine (Hatanaka et al, 2001; Ling et al, 2001). Present on the abluminal membrane of brain endothelial cells, this system also may contribute to the regulation of the osmolarity in the brain and cell volume (Hatanaka et al, 2001; Ohtsuki, 2004).
The organic anion transporter (OAT) family is also involved in efflux transport at the BBB. These transporters are involved in the efflux of various neurotransmitter metabolites and act as a CNS detoxification system (Ohtsuki et al, 2004). For example, OAT3 (SLC22A8), localized at the abluminal membrane, transports homovanillic acid (HVA) from brain to blood (Mori et al, 2003; Ohtsuki et al, 2002). OAT3-mediated HVA transport is inhibited by various neurotransmitter metabolites such as 3,4-dihydroxyphenylacetic acid (dopamine metabolite), vanillylmandelic acid, 3,4-dihydroxymandelic acid and 4-hydroxy-3-methoxyphenylglycol (norepinephrine and epinephrine metabolites), 5-hydroxyindole acetic acid and 5-methoxytryptophol (serotonin metabolites), and imidazole-4-acetic acid and 1-methyl-4-imidazolic acid (histamine metabolites) (Duan & Wang, 2010; Ohtsuki et al, 2002). Thus it appears that OAT3 mediates the clearance of a wide range of neurotransmitter metabolites from brain. In addition, OAT3 mediates the brain-to-blood efflux of indoxyl sulfate, a uremic toxin (Ohtsuki et al, 2002). The brain concentration of under normal conditions is 3.4 times lower than that in serum and this limited distribution could be due to OAT3-mediated BBB efflux (Ohtsuki et al, 2002).
Another transporter of organic anions, Oatp2, is localized on both the luminal and abluminal membrane of brain endothelial cells and plays a role in the efflux of dehydroepiandrosterone sulfate, a neurosteroid that can interact with GABA type A receptors and σ receptors to increase memory and learning ability and to protect neurons against excitatory amino acid-induced neurotoxicity (Asaba et al, 2000; Gao et al, 1999; Ose et al, 2010). Oatp2 is also responsible for estrone-3-sulfate efflux transport (Asaba et al, 2000).
BBB active drug efflux transporters know as ATP-binding cassette (ABC) efflux transporters are increasingly recognized as important determinants of drug distribution to, and elimination from, the brain, minimizing or avoiding in this way neurotoxic adverse effects of drugs that otherwise would penetrate into the brain (Begley, 2004). Until now the best characterized of the BBB ABC efflux transporters are P-glycoprotein (Pgp, ABCB1), the multidrug resistance associated protein MRP (ABCC2) family and breast cancer resistance protein (BCRP) (Eisenblätter et al, 2003; Virgintino et al, 2002; Zhang et al, 2003).
P-glycoprotein (P-gp/MDR1/ABCB1) is a well-characterized efflux transporter of xenobiotics (Löscher et al, 2005). P-gp is a primary active transporter of relatively lipophilic compounds, such as the anticancer drug, vinblastine, cyclosporin A, and the cardiac glycoside, digoxin, by direct consumption of ATP (Hembury et al, 2008; Löscher et al, 2005; Quezada et al, 2008; van der Sandt et al, 2001). In addition, P-gp contributes to efflux of such as amyloid-beta proteins from the brain into the blood as well as many drugs such as anti-cancer drugs (Cirrito et al, 2005; Nazer et al, 2008; Piwnica-Worms et al, 2006). P-gp expressed on the luminal side of brain endothelial cells plays a very important role in restricting the entry of xenobiotics from the circulating blood into the brain (Matsuoka et al, 1999, Warren et al, 2009). Thus, for example, ivermectin reaches 20-fold higher concentrations in the brains of mice without P-gp (Lespine et al, 2006).
The multidrug resistance-associated protein (MRP) 1, 4, 5, and 6 has been detected in primary cultured bovine brain endothelial cells and the bovine brain capillary-enriched fraction (Nies et al, 2004; Yu et al, 2007; Zhang et al, 2000). MRP1 and 5 are predominantly localized on the luminal membrane fraction while MRP4 is localized almost equally on the luminal and abluminal membrane fractions (Nies et al, 2004; Yu et al, 2007). However, the localization of these subtypes is still unclear. Although the full functions of MRPs are still unknown (and the relative importance still debated), one recent study indicated that Mrp1 contributes in part to the efflux transport of Estradiol-17-β-D-glucuronide (E217βG) at the BBB (Sugiyama et al, 2003) (Fig. 3).
4. BBB and epilepsy
Epilepsy is a chronic neurological disease that is characterized by spontaneous recurrent seizures and sometimes-untreatable seizures. In addition, epileptogenesis can occur after brain insults such as trauma, ischemia and infection. Several clinical and experimental studies have reported that BBB malfunction can trigger chronic seizures or an acute seizure (Friedman et al, 2009; Oby & Janigro, 2006; Tomkins et al 2011). Furthermore, transient BBB disruption is a consequence of epileptic seizures and multiple changes in BBB transporters have been reported in epilepsy patients/models. BBB obviously play an important multifaceted role in epileptic seizures as discussed below (Dombrowski et al, 2001; Löscher et al, 2002; Łotowska et al, 2008).
Pathological and immunohistochemical studies in human epileptic tissue as well as animal models of epilepsy consistently demonstrate structural evidence for an abnormal “leaky” BBB with an accumulation of serum albumin within the neuropil and cellular elements as functional evidence for abnormal vessels permeability to large hydrophilic molecules (Oby & Janigro, 2006; Stewart et al, 1987). A substantial increase in BBB permeability was found in approximately 2/3 of capillaries and perivascular astroglial processes.
4.1. Blood Brain Barrier permeability and epilepsy
Increased BBB permeability is associated with remodeling of interendothelial junctional complex and gap formation between brain endothelial cells (paracellular pathway) and/or intensive pinocytotic vesicular transport between the apical and basal side of brain endothelial cells (transcellular pathway) (Bazzoni, 2006; Garcia & Schaphorst, 1995; Lossinsky & Shivers, 2004). These two pathways display differences in cellular and molecular components as well as in physical properties. The transcellular pathway can be either passive or active, and is characterized by low conductance and high selectivity in either apical to basal or basal to apical directions. In contrast, the paracellular pathway is exclusively passive, being driven by electrochemical and osmotic gradients, and it shows a higher conductance and lower selectivity, although it can display charge and size selectivity (Bazzoni, 2006). There is evidence that both types of pathway are involved in the development and progression of epilepsy seizures. Ultrastructural studies on human epileptic tissue clearly demonstrated BBB abnormalities, including increased micropinocytosis and fewer mitochondria in endothelial cells, a thickening of the basal membrane, and the presence of abnormal tight junctions (Cornford & Hyman, 1999; Cornford & Oldendorf, 1986).
Increased BBB permeability could be an etiological factor contributing to seizure development. Both clinical and animal studies pinpoint that primary vascular lesions and, specifically an opening of the BBB (i.e. significant and long-lasting BBB breakdown in cortical injury), trigger a chain of events leading to epilepsy (Marchi et al, 2007; Oby and Janigro, 2006; Seiffert et al, 2004; Tomkins et al, 2007; Tomkins et al, 2008; van Vliet et al, 2007). Increased BBB permeability was found in 77% of patients with posttraumatic epilepsy and these patents had a larger cerebral cortex volume with BBB disruption (Tomkins et al, 2008). In 70% of patients, slow (delta band) activity was co-localized, by sLORETA, with regions showing BBB disruption (Tomkins et al, 2011). A consequence of increased para- and transcellular permeability is extravasation of albumin into the brain neuropil. This may be sufficient for the induction of epileptogenesis. It has been suggested that accumulated albumin binds to transforming growth factor beta receptor 2 (TGFbetaR2) in astrocytes and induces rapid astrocytic transformation and dysfunction (Cacheaux et al, 2009; David et al, 2009; Ivens et al, 2007) In addition, leakage of some other serum-derived components into the extracellular space may also result in hyperexcitability and seizure onset. For example, it has been recently shown that the serum protein, thrombin, via receptors protease-activated receptor 1 (PAR1), produces a long-lasting enhancement of the reactivity of CA1 neurons to afferent stimulation (Maggio et al, 2008). It should also be noted that in many cases of epilepsy, that BBB breakdown has been associated with early or delayed neuronal damage (Rigau et al, 2007; Tomkins et al, 2007; van Vliet et al, 2007).
Furthermore, BBB dysfunction may not only trigger epileptic seizures, it may also contribute to the progression of epilepsy (Seiffert et al, 2004, van Vliet et al, 2007; Uva et al, 2008). Recently, a role for BBB opening in the progression of temporal epilepsy was suggested based on the finding of positive immunocytochemistry staining for accumulated albumin and a positive correlation between the extent of BBB opening and the number of seizures (van Vliet et al, 2007). In the line with that evidence, application of bile salts causes long-lasting BBB opening caused by application of bile salts and the delayed appearance of robust hypersynchronous epileptiform activity (Greenwood et al, 1991). Predictors of seizures during the BBB breakdown are elevation of serum S100beta (an astrocyte marker) levels and computed tomography (CT) scans (Marchi et al, 2007).
Vasogenic brain edema is one the best example of association between BBB dysfunction and epilepsy. In experimental epilepsy models (kainate- and pilocarpine-epilepsy models, layers II and III of the piriform cortex are vulnerable to brain edema and they have been shown to play a role in generation and propagation of paroxysmal activity (Gale, 1992, Löscher and Ebert, 1996, McIntyre and Kelly, 2000). In contrast to the piriform cortex, the hippocampus shows vacuolized CA1 astrocytes and neuronal death without vasogenic edema (Kim et al, 2009, Kim et al, 2010).
Many studies have reported an increased permeability of the BBB during epileptic activity (Öztas and Kaya, 1991, Ruth, 1984; Ilbay et al, 2003, Ates et al, 1999). A fast and significant increase in systemic blood pressure, particularly during tonic epileptic seizures, induces marked vasodilation of large cerebral arteries and an increase in blood pressure in capillaries, small arteries, and veins, leading to leakage of the BBB (Mayhan, 2001). Indeed, an acute increase in blood pressure or epileptic activity causes increased pinocytosis in the cerebral endothelium (Cornford and Oldendorf, 1986).
The loss of BBB integrity, however, is not only due to an abrupt increase in intraluminal pressure but also influenced by the properties of cerebral tissues, particularly in the perivascular area (Nitsch et al, 1985). The most notable changes are on perivascular astrocytes. Several recent studies have pinpointed alterations in astrocytic dystrophin expression during epileptogenesis, which may directly influence brain endothelial barrier permeability. Dystrophin, an actin-binding protein, is primarily localized in the astrocyte end-feet near capillaries where this anchor protein is responsible for maintenance of polarized expression of astrocytic aquaporin 4 (AQP4; a water channel) (Nico et al, 2003; Sheen et al, 2011). Since astrocytes selectively control exchange between blood and neural tissue by induction of the morphological and biochemical features of endothelial cells to form TJ and of its enzymatic systems and transporters, it is likely that dystrophin plays a role in establishment of endothelial polarity and regulating vascular permeability (Anderson et al, 1989; Nico et al, 2003). However, some dystrophin isoforms are also present in brain endothelial cells where, as an actin binding protein, dystrophin may regulate the actin machinery associated with the TJ complex (Nico et al, 2004). During epileptogenesis, there is down-regulation of dystrophin immunoreactivity in perivascular astrocytes and endothelial cells and this was also accompanied by impaired AQP4 expression in perivascular astroglial end-feet. The perturbed expression of AQP4 and dystrophin furthermore may be one factor underlying loss of ion and water homeostasis in the epileptic brain tissue, leading to impaired buffering of extracellular K+ and an increased propensity for seizures (Lee et al, 2004, Eid et al, 2005).
SMI-7 is an endothelial barrier antigen expressed on the luminal membrane at the rat BBB (Sternberger & Sternberger, 1987). SMI-71 immunoreactivity is also significantly reduced in blood vessels at day 1 after epileptogenesis when the neuronal damage is also present (Lu et al, 2010). However, the down-regulation of SMI-71 is also associated with widening of intercellular junctions between endothelial cells and swelling of perivascular astrocytic processes and this was caused by impaired interaction between endothelial cells and perivascular astrocytes (Ghabriel et al, 2002; Lawrenson et al, 1995).
4.2. Angiogenesis, blood brain barrier and epilepsy
In humans, there is evidence that cerebral vascularization (vessel density) is significantly higher in temporal lobe epilepsy (Rigau et al, 2007). This was neither dependent on etiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. Vascular endothelial growth factor (VEGF) and the VEGF receptors were detected in different types of cells suggesting a role of this growth factor in the increased vascularization. In that study, an impairment of the BBB was demonstrated by a loss of TJs and by immunoglobulin G (IgG) leakage and accumulation in neurons. In a rat model of temporal lobe epilepsy, VEGF over-expression and BBB impairment also occurred early after status epilepticus (Croll et al; 2004 Nicoletti et al, 2008). This was followed by a progressive increase in vascularization. In both humans and rodents, the processes of angiogenisis and BBB disruption were still obvious in the chronic focus, probably the result of recurrent seizures (Marcon et al, 2009; Ndode-Ekane et al, 2010).
4.3. Inflammation, blood brain barrier and epilepsy
Several proinflammatory signals are rapidly induced in rodent brain during epileptic activity. These include cytokines, chemokines, prostaglandins, toll-like receptors, signal-transduction pathways that recruit nuclear factor-κB (NF-κB), complement factors and cell-adhesion molecules (Alapirtti et al, 2009; Avignone et al, 2008; Gorter et al, 2006; Manley et al, 2007; Natoli et al, 2000; Oliveira et al, 2008; Sinha et al, 2008; Zattoni et al, 2011). Seizures induce a massive inflammatory response in parenchymal cells, involving both microglia and neurons (Riazi et al, 2008, Zattoni et al, 2011).
Inflammation might either contribute to epileptogenesis or be a response that develops after seizures. There is substantial evidence supporting both CNS and intravascular inflammation as being seizure promoting or pro-epileptogenic. BBB damage is known to directly cause seizures and to increase spontaneous seizure frequency (Rossi et al, 2011; Riazi et al, 2008; Vezzani et al, 2011,; Zattoni et al, 2011). Blockade of CNS or systemic inflammation pathways (e.g., via inhibition of interleukin [IL]-1β signaling with IL1-receptor antagonist or via blockade of IL-1β production with caspase-1 inhibitors) reduces status epilepticus and seizure frequency (Alapirtti et al, 2009; Gorter et al, 2006; Kim et al, 2010; Vezzani et al, 2010). Glia, neurons, and endothelial cells express cytokines following seizures in experimental models in human epileptogenic tissue and after brain injury (Rossi et al, 2011; Sinha et al, 2008). These findings point to a prominent role for cytokines in the pathogenesis of seizures. Elucidation of the mechanisms underlying the effects of cytokines in seizures highlights nonconventional modes of action involving direct effects on neuronal excitability or a direct action on BBB integrity.
Seizures also, however, induce elevated expression of vascular cell adhesion molecules and enhance leukocyte rolling and arrest in brain vessels, effects mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by
Taking into consideration all of these data, there is a need for the development of strategies to detect BBB permeability changes for diagnosis (i.e. to identify the epileptic region prior to surgery) and for targeting populations at risk of developing epilepsy. A diagnostic tool for measuring BBB permeability should give reliable, objective and quantitative information with high spatial resolution. Qualitative evaluation of BBB disruption in humans accompanied with analysis of the cerebrospinal fluid for serum proteins or peripheral blood for brain constituents (e.g. S100β) could be promising strategies (Marchi et al., 2003).
4.4. Blood Brain Barrier transporters and epilepsy
Changes in BBB transporter systems also play an important role in epilepsy. It is estimated that 20-25% of epileptic patients fail to achieve good control with the different antiepileptic drugs treatments, developing so-called refractory epilepsy. Changes in ABC transporters like P-gp, MRPs (MRP1 and MRP2) and BCRP are directly related with the refractoriness (Abbott et al, 2007; Dombrowski et al, 2001; Lazarowski et al, 2007; Liu et al, 2000; Löscher &Potschka, 2002). These transporters are overexpressed in the brains of patients with refractory epilepsy, with implications for active drug efflux from brain. The progressive neuronal P-gp expression, depending on intensity and time-constancy of seizure-injury, is in agreement with the development of "P-gp-positive seizure-axis" proposed by Kwan & Brodie, who also showed that the development of refractory epilepsy directly correlated with the number and frequency of seizures before initiation of drug therapy (Kwan & Brodie, 2005). Furthermore two recent studies highlighted a possible underlying mechanism of the increased Pgp protein expression during the seizures. The studies by Bauer and colleagues and Hartz and colleagues have indicated that NMDA receptor, cyclooxygenase-2 (COX-2) prostaglandin E2and NFκB are involved in increase expression of Pgp on brain microvascular endothelial cells and subsequently with that specific COX-2 inhibitor, NMDA receptor antagonist and E2 receptor antagonist abolished seizers dependent increase in Pgp expression (Bauer et al, 2008; Hartz et al, 2006). Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.
Another transporter prominent expressed in epilepsy is GLUT-1. GLUT-1 immunoreactivity is increased in blood vessels after status epilepticus and after kainic acid- or pentylenetetrazole-induced seizures (Cornford et al, 2000; Gronlund et al, 1996). As there is a rapid increase in neuronal metabolic energy demands during seizures (Gronlund et al, 1996), this indicates that GLUT-1 may be upregulated under conditions of elevated brain glucose metabolism. Alternatively, alteration in GLUT-1 expression may be relevant to angiogenesis, which contributes to epileptogenesis and/or ictogenesis in experimental and human epilepsy (Ndode-Ekane et al, 2010, Marcon et al, 2009).
The data from experimental animals and human clinical studies indicate that studying mechanisms underlying epileptogenesis and epileptic seizures must consider variety of interactions within the “neurovascular unit”. Significant changes occur in the vascular system, astrocytes and microglia cells which contribute significantly to the pathogenesis of the disease. Recent advances in imaging indicate that identification and quantification of such events are in hand and call for large-scale prospective studies to explore the role of BBB breakdown in the epileptogenic process. Valuable information on the time resolution and extent of BBB permeability changes, the role of astrocytes, inflammation and specific molecular pathways in human epileptogenesis, may allow a better design of anti-epileptogenic and anti-epileptic treatments for specific populations.
Abbott N. J. 2002Astrocyte-endothelial interactions and blood-brain barrier permeability. , 200 6 629 638
Abbott N. J. Khan E. U. Rollinson C. M. Reichel A. Janigro D. Dombrowski S. M. Dobbie M. S. Begley D. J. 2002Drug resistance in epilepsy: the role of the blood-brain barrier. 243 38 47
Alapirtti T. Rinta S. Hulkkonen J. Mäkinen R. Keränen T. Peltola J. 2009Interleukin-6, interleukin-1 receptor antagonist and interleukin-1beta production in patients with focal epilepsy: A video-EEG study. , 280 1-2 94 97
Anderson P. N. Woodham P. Turmaine M. 1989Peripheral nerve regeneration through optic nerve grafts. , 77 5 525 534
Andreeva A. Y. Piontek J. Blasig I. E. Utepbergenov D. I. 2006Assembly of tight junction is regulated by the antagonism of conventional and novel protein kinase C isoforms. ., 38 2 222 233
Armulik A. Genové G. Mäe M. Nisancioglu M. H. Wallgard E. Niaudet C. He L. Norlin J. Lindblom P. Strittmatter K. Johansson B. R. Betsholtz C. 2010Pericytes regulate the blood-brain barrier. 468 7323 557 561
( Asaba H. Hosoya K. Takanaga H. Ohtsuki S. Tamura E. Takizawa T. Terasaki T. 2000). Blood-brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2. Journal of Neurochemistry, 5 75 1907 EOF 16 EOF
Ates N. Esen N. Ilbay G. 1999Absence epilepsy and regional blood-brain barrier permeability: the effects of pentylenetetrazole-induced convulsions. , 39 4 305 310
Avignone E. Ulmann L. Levavasseur F. Rassendren F. Audinat E. 2008Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. . 28 37 9133 9144
Audus K. L. Borchardt R. T. 1986Characteristics of the large neutral amino acid transport system of bovine brain microvessel endothelial cell monolayers. . 47 2 484 488
Batrakova E.V. Zhang Y. Li Y. Li S. Vinogradov S.V. Persidsky Y. Alakhov V.Y. Miller D.W. ( Kabanov A.V. 2004). Effects of pluronic P85 on GLUT1 and MCT1 transporters in the blood-brain barrier. Pharmacological Research. 11 21 1993 2000
Bauer B. Hartz A. M. Pekcec A. Toellner K. Miller D. S. Potschka H. 2008Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. . 73 5 1444 1453
Bazzoni G. Dejana E. 2004Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. ., 84 3 869 901
Bazzoni G. Martinez-Estrada O. M. Mueller F. Nelboeck P. Schmid G. Bartfai T. Dejana E. Brockhaus M. 2000Homophilic interaction of junctional adhesion molecule. 274 40 30970 30976
Bazzoni G. 2006Endothelial tight junctions: permeable barriers of the vessel wall. ., 95 1 36 42
Begley D. J. 2004ABC transporters and the blood-brain barrier. . 10 12 1295 1312
Belanger M. Asashima T. Ohtsuki S. Yamaguchi H. Ito S. Terasaki T. 2007Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. ., 50 1 95 101
Boado R. J. Li J. Y. Nagaya M. Zhang C. Pardridge W. M. 1999Selective expression of the large neutral amino acid transporter at the blood-brain barrier. , 96 21 12079 12084
Bourasset F. Cisternino S. Temsamani J. Scherrmann J. M. 2003Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier. . 86 6 1564 1567
Braissant O. Henry H. Loup M. Eilers B. Bachmann C. 2001Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. . 86 1-2 193 201
Broadwell R. D. Baker-Cairns B. J. Friden P. M. Oliver C. Villegas J. C. 1996Transcytosis of protein through the mammalian cerebral epithelium and endothelium. III. Receptor-mediated transcytosis through the blood-brain barrier of blood-borne transferrin and antibody against the transferrin receptor. . 142 1 47 65
Butt A. M. Jones H. C. Abbott N. J. 1990Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. . 429 47 62
Cacheaux L. P. Ivens S. David Y. Lakhter A. J. Bar-Klein G. Shapira M. Heinemann U. Friedman A. Kaufer D. 2009Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. . 29 28 8927 8935
Cansev M. 2006Uridine and cytidine in the brain: their transport and utilization. . 52 2 389 397
Cornford E. M. Nguyen E. V. Landaw E. M. 2000Acute upregulation of blood-brain barrier glucose transporter activity in seizures. . 279 3 H1346 H1354
Croll S. D. Goodman J. H. Scharfman H. E. 2004Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword. . 548 57 68
Cirrito J. R. Deane R. Fagan A. M. Spinner M. L. Parsadanian M. Finn M. B. Jiang H. Prior J. L. Sagare A. Bales K. R. Paul S. M. Zlokovic B. V. Piwnica-Worms D. Holtzman D. M. 2005P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. . 115 11 3285 3290
Citi S. Cordenonsi M. 1998Tight junction proteins. , 1448 1 1 11
Clump D. A. Qazi I. H. Sudol M. Flynn D. C. 2005c-Yes response to growth factor activation. , 23 4 263 272
Cornford E. M. Oldendorf W. H. 1986Epilepsy and the blood-brain barrier. . 44 787 812
Cornford E. M. Hyman S. 1999Blood-brain barrier permeability to small and large molecules. . 36 2-3 145 163
Cornford E. M. Young D. Paxton J. W. Hyman S. Farrell C. L. Elliott R. B. 1993Blood-brain glucose transfer in the mouse. . 18 5 591 597
Crone C. Christensen O. 1981Electrical resistance of a capillary endothelium. . 77 4 349 371
David Y. Cacheaux L. P. Ivens S. Lapilover E. Heinemann U. Kaufer D. Friedman A. 2009Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? . 29 34 10588 10599
Denker B. M. Nigam S. K. 1998Molecular structure and assembly of the tight junction. . 274 F1 F9
Dombrowski S. M. Desai S. Y. Marroni M. Cucullo L. Goodrich K. Bingaman W. Mayberg M. R. Bengez L. Janigro D. 2001Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. . 42 12 1501 1506
Duan H. Wang J. 2010Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. . 335 3 743 753
Dudek S. M. Garcia J. G. 2001Cytoskeletal regulation of pulmonary vascular permeability. . 91 4 1487 1500
Eid T. Lee T. S. Thomas M. J. Amiry-Moghaddam M. Bjørnsen L. P. Spencer D. D. Agre P. Ottersen O. P. de Lanerolle N. C. 2005Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. . 102 4 1193 1198
Eisenblätter T. Hüwel S. Galla H. J. 2003Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood-brain barrier. . 971 2 221 231
Ehrlich P. 1885Das sauerstufbudurfnis des organismus, in Eine Farbenanalytische Studie, Hirschwald, Berlin.
Ennis S. R. Kawai N. Ren X. D. Abdelkarim G. E. Keep R. F. 1998Glutamine uptake at the blood-brain barrier is mediated by N-system transport. . 71 6 2565 2573
Fabene P. F. Navarro G. Mora M. Martinello B. Rossi F. Merigo L. Ottoboni S. Bach S. Angiari D. Benati A. Chakir L. Zanetti F. Schio A. Osculati P. Marzola E. Nicolato J. W. Homeister L. Xia J. B. Lowe R. P. Mc Ever F. Osculati A. Sbarbati E. C. Butcher G. Constantin 2008A role for leukocyte-endothelial adhesion mechanisms in epilepsy. . 14 12 1377 1383
Fanning A. S. Little B. P. Rahner C. Utepbergenov D. Walther Z. Anderson J. M. 2007The unique-5 and-6 motifs of ZO-1 regulate tight junction strand localization and scaffolding properties. , 18 3 721 731
Feldman G. J. Mullin J. M. Ryan M. P. 2005Occludin: structure, function and regulation. ., 57 6 883 917
Friedman A. Kaufer D. Heinemann U. 2009Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy. . 85 2-3 142 149
Gale K. 1992Subcortical structures and pathways involved in convulsive seizure generation. . 9 2 264 277
Gao B. Hagenbuch B. Kullak-Ublick G. A. Benke D. Aguzzi A. Meier P. J. 2000Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. . 294 1 73 79
Gao B. Stieger B. Noé B. Fritschy J. M. Meier P. J. 1999Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. . 47 10 1255 1264
Garcia J. G. Schaphorst K. L. 1995Regulation of endothelial cell gap formation and paracellular permeability. ., 43 117 126
Gibbs J. P. Adeyeye M. C. Yang Z. Shen D. D. 2004Valproic acid uptake by bovine brain microvessel endothelial cells: role of active efflux transport. . 58 1 53 66
( Girod J. Fenart L. Régina A. Dehouck M.P. Hong G. Scherrmann J.M. Cecchelli R. Roux F. 1999). Transport of cationized anti-tetanus Fab’2 fragments across an in vitro blood-brain barrier model: involvement of the transcytosis pathway. Journal of Neurochemistry. 5 73 2002 2008
Goldmann E. E. 1913Vitalfarbung am zentralnervensystem. Abhandl Konigl preuss Akad Wiss 1 1 60
Gonzalez-Mariscal L. Betanzos A. Avila-Flores A. 2000MAGUK proteins: structure and role in the tight junction. . 11 4 315 324
Gonzalez-Mariscal L. Betanzos A. Nava P. Jaramillo B. E. 2003Tight junction proteins. ., 81 1 1 44
Gorter J. A. van Vliet E. A. Aronica E. Breit T. Rauwerda H. Lopes F. H. da Silva. W. J. Wadman 2006Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. . 26 43 11083 11110
Ghabriel M. N. Zhu C. Leigh C. 2002Electron microscope study of blood-brain barrier opening induced by immunological targeting of the endothelial barrier antigen. . 934 2 140 151
Greenwood R. S. Meeker R. B. Hayward J. N. 1991Amygdala kindling elevates plasma vasopressin. . 538 1 9 14
Gronlund K. M. Gerhart D. Z. Leino R. L. Mc Call A. L. Drewes L. R. 1996Chronic seizures increase glucose transporter abundance in rat brain. . 55 7 832 840
Hamazaki Y. Itoh M. Sasaki H. Furuse M. Tsukita S. 2002Multi-PDZ domain protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. . 277 1 455 461
Hartz A. M. Bauer B. Fricker G. Miller D. S. 2006Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. . 69 2 462 470
Hatanaka T. Huang W. Martindale R. G. Ganapathy V. 2001Differential influence of cAMP on the expression of the three subtypes (ATA1, ATA2, and ATA3) of the amino acid transport system A. . 505 2 317 320
Hatzfeld M. 2005The p120 family of cell adhesion molecules. 84 2-3 205 214
Hawkins B. T. Davis T. P. 2005The blood-brain barrier/neurovascular unit in health and disease. . 57 2 173 185
Hembury A. Mabondzo A. 2008Endothelin-1 reduces p-glycoprotein transport activity in an in vitro model of human adult blood-brain barrier. . 28 7 915 921
Hervé F. Ghinea N. Scherrmann J. M. 2008CNS delivery via adsorptive transcytosis. . 10 3 455 472
Hommelgaard A. M. Roepstorff K. Vilhardt F. Torgersen M. L. Sandvig K. van Deurs B. 2005Caveolae: stable membrane domains with a potential for internalization. . 6 9 720 724
Honore S. Pasquier E. Braguer D. 2005Understanding microtubule dynamics for improved cancer therapy. ., 62 24 3039 3056
Huber J. D. Egleton R. D. Davis T. P. 2001Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. 24 12 719 725
Ilbay G. Sahin D. Ates N. 2003Changes in blood-brain barrier permeability during hot water-induced seizures in rats. . 24 4 232 235
Ivens S. Kaufer D. Flores L. P. Bechmann I. Zumsteg D. Tomkins O. Seiffert E. Heinemann U. Friedman A. 2007TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. 130 2 535 547
Kakee A. Takanaga H. Terasaki T. Naito M. Tsuruo T. Sugiyama Y. 2001Efflux of a suppressive neurotransmitter, GABA, across the blood-brain barrier. 79 1 110 118
Kang Y. S. Ohtsuki S. Takanaga H. Tomi M. Hosoya K. Terasaki T. 2002Regulation of taurine transport at the blood-brain barrier by tumor necrosis factor-alpha, taurine and hypertonicity. . 83 5 1188 1195
Kido Y. Tamai I. Okamoto M. Suzuki F. Tsuji A. 2000Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier using in vitro cultured cells and in vivo BUI studies. . 17 1 55 62
Kim J. E. Choi H. C. Song H. K. Jo S. M. Kim D. S. Choi S. Y. Kim Y. I. Kang T. C. 2010Levetiracetam inhibits interleukin-1 beta inflammatory responses in the hippocampus and piriform cortex of epileptic rats. . 471 2 94 99
Kim J. H. Kim J. H. Park J. A. Lee S. W. Kim W. J. Yu Y. S. Kim K. W. 2006Blood-neural barrier: intercellular communication at glio-vascular interface. . 39 4 339 345
Kim D. W. Lee S. K. Nam H. Chu K. Chung C. K. Lee S. Y. Choe G. Kim H. K. 2010Epilepsy with dual pathology: surgical treatment of cortical dysplasia accompanied by hippocampal sclerosis. 51 8 1429 1435
Kim J. E. Ryu H. J. Yeo S. I. Seo C. H. Lee B. C. Choi I. G. Kim D. S. Kang T. C. 2009Differential expressions of aquaporin subtypes in astroglia in the hippocampus of chronic epileptic rats. . 163 3 781 789
Kirkham M. Parton R. G. (2005 2005Clathrin-independent endocytosis: new insights into caveolae and non-caveolar lipid raft carriers. . 1745 3 273 286
Koval M. 2006Claudins--key pieces in the tight junction puzzle. . 13 3 127 138
Kwan P. Brodie M. J. 2005Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. . 46 2 224 223
Lai C. H. Kuo K. H. Leo J. M. 2005Critical role of actin in modulating BBB permeability. . 50 1 7 13
Lamagna C. Meda P. Mandicourt G. Brown J. Gilbert R. J. Jones E. Y. Kiefer F. Ruga P. Imhof B. A. Aurrand-Lions M. 2005Dual interaction of JAM-C with JAM-B and alpha(M)beta2 integrin: function in junctional complexes and leukocyte adhesion. 16 10 4992 5003
Lampugnani M. G. Orsenigo F. Rudini N. Maddaluno L. Boulday G. Chapon F. Dejana E. 2010CCM1 regulates vascular-lumen organization by inducing endothelial polarity. , 123Pt 7, 1073 1080
Lawrenson J. G. Ghabriel M. N. Reid A. R. Gajree T. N. Allt G. 1995Differential expression of an endothelial barrier antigen between the CNS and the PNS. , 186Pt 1, 217 221
Lazarowski A. Czornyj L. Lubienieki F. Girardi E. Vazquez S. D’Giano C. 2007ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. , 48Suppl 5, 140 149
Lee T. S. Eid T. Mane S. Kim J. H. Spencer D. D. Ottersen O. P. de Lanerolle N. C. 2004Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy. , 108 6 493 502
Lespine A. Dupuy J. Orlowski S. Nagy T. Glavinas H. Krajcsi P. Alvinerie M. 2006Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3). , 159 3 169 179
Li J. Y. Boado R. J. Pardridge W. M. 2001Cloned blood-brain barrier adenosine transporter is identical to the rat concentrative Na+ nucleoside cotransporter CNT2. . 21 8
Li Y. Fanning A. S. Anderson J. M. Lavie A. 2005Structure of the conserved cytoplasmic C-terminal domain of occludin: identification of the ZO-1 binding surface. . 352 1 151 164
Librizzi L. Regondi M. C. Pastori C. Frigerio S. Frassoni C. de Curtis M. 2007Expression of adhesion factors induced by epileptiform activity in the endothelium of the isolated guinea pig brain in vitro. . 48 4 743 751
Ling R. Bridges C. C. Sugawara M. Fujita T. Leibach F. H. Prasad P. D. Ganapathy V. 2001Involvement of transporter recruitment as well as gene expression in the substrate-induced adaptive regulation of amino acid transport system A. . 1512 1 15 21
Liu Y. Hu M. 2000P-glycoprotein and bioavailability-implication of polymorphism. , 38 9 877 881
Löscher W. Ebert U. 1996The role of the piriform cortex in kindling. . 50 5-6 427 481
Löscher W. Potschka H. 2002Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. . 301 1 7 14
Löscher W. Potschka H. 2005Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. . 2 1 86 98
Lossinsky A. S. Shivers R. R. 2004Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. . 19(2), 535-564.
Lossinsky A. S. Vorbrodt A. W. Wisniewski H. M. 1983Ultracytochemical studies of vesicular and canalicular transport structures in the injured mammalian blood-brain barrier. (Berlin), 61 3-4 239 245
Łotowska J. M. Sobaniec-Łotowska M. E. Sendrowski K. Sobaniec W. Artemowicz B. 2008Ultrastructure of the blood-brain barrier of the gyrus hippocampal cortex in an experimental model of febrile seizures and with the use of a new generation antiepileptic drug--topiramate. , 46 1 57 68
Lu H. Demny S. Zuo Y. Rea W. Wang L. Chefer S. I. Vaupel D. B. Yang Y. Stein E. A. 2010Temporary disruption of the rat blood-brain barrier with a monoclonal antibody: a novel method for dynamic manganese-enhanced MRI. . 50 1 7 14
Luer M. S. Hamani C. Dujovny M. Gidal B. Cwik M. Deyo K. Fischer J. H. 1999Saturable transport of gabapentin at the blood-brain barrier. , 21 6 559 562
Lyck R. Ruderisch N. Moll A. G. Steiner O. Cohen C. D. Engelhardt B. Makrides V. Verrey F. 2009Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo. . 29 9 1491 1502
Maggio N. Shavit E. Chapman J. Segal M. 2008Thrombin induces long-term potentiation of reactivity to afferent stimulation and facilitates epileptic seizures in rat hippocampal slices: toward understanding the functional consequences of cerebrovascular insults. , 28 3 732 736
Manley N. C. Bertrand A. A. Kinney K. S. Hing T. C. Sapolsky R. M. 2007Characterization of monocyte chemoattractant protein-1 expression following a kainate model of status epilepticus. , 1182 138 143
Marchi N. Angelov L. Masaryk T. Fazio V. Granata T. Hernandez N. Hallene K. Diglaw T. Franic L. Najm I. Janigro D. 2007Seizure-promoting effect of blood-brain barrier disruption. , 48 4 732 742
Marcon J. Gagliardi B. Balosso S. Maroso M. Noé F. Morin M. Lerner-Natoli M. Vezzani A. Ravizza T. 2009Age-dependent vascular changes induced by status epilepticus in rat forebrain: implications for epileptogenesis. . 34 1 121 132
Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. 1998Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. 142 1 117 127
Masand G. Hanif K. Sen S. Ahsan A. Maiti S. Pasha S. 2006Synthesis, conformational and pharmacological studies of glycosylated chimeric peptides of Met-enkephalin and FMRFa. . 68 5 329 334
Matsuoka Y. Okazaki M. Kitamura Y. Taniguchi T. 1999Developmental expression of P-glycoprotein (multidrug resistance gene product) in the rat brain. . 39 3 383 392
Mayhan W. G. 2001Regulation of blood-brain barrier permeability. , 8 2 89 104
Mc Allister M. S. Krizanac-Bengez L. Macchia F. Naftalin R. J. Pedley K. C. Mayberg M. R. Marroni M. Leaman S. Stanness K. A. Janigro D. 2001Mechanisms of glucose transport at the blood-brain barrier: an in vitro study. , 904 1 20 30
Mc Intyre D. C. Kelly M. E. 2000The parahippocampal cortices and kindling. . 911 343 354
( McNeil E. Capaldo C.T. Macara I.G. 2006). Zonula occludens-1 function in the assembly of tight junctions in Madin-Darby canine kidney epithelial cells. Molecular Biology of the Celll. 4 17 1922 1932
Meyer T. N. Hunt J. Schwesinger C. Denker B. M. 2003Galpha12 regulates epithelial cell junctions through Src tyrosine kinases. . 285 5 C1281 C1293
Mitic L. L. Aderon J. M. 1998Molecular architecture of tight junctions. , 60 121 142
Miwako I. Schroter T. Schmid S. L. 2003Clathrin- and dynamin-dependent coated vesicle formation from isolated plasma membranes. . 4 6 376 389
Mori S. Takanaga H. Ohtsuki S. Deguchi T. Kang Y. S. Hosoya K. Terasaki T. 2003Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. 23 4 432 440
Morita K. Sasaki H. Furuse M. Tsukita S. 1999Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. , 147 1 185 194
Mukherjee S. Ghosh R. N. Maxfield F. R. 1997Endocytosis. . 77 3 759 803
Nagafuchi A. 2001Molecular architecture of adherens junctions. Current Opinion in Cell Biology, 13 600 603
( Nakatani Y. Sato-Suzuki I. Tsujino N. Nakasato A. Seki Y. Fumoto M. Arita H. 2008). Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat. European Journal of Neuroscience, 9 27 2466 2472
Natoli M. Montpied P. Rousset M. C. Bockaert J. Rondouin G. 2000NFkappaB by hippocampal cells in excitotoxicity and experimental epilepsy. . 41 2 141 154
Nazer B. Hong S. Selkoe D. J. 2008LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model. , 30 1 94 102
Nico B. Frigeri A. Nicchia G. P. Corsi P. Ribatti D. Quondamatteo F. Herken R. Girolamo F. Marzullo A. Svelto M. Roncali L. 2003Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. , 42 3 235 251
Nico B. Paola-Nicchia G. Frigeri A. Corsi P. Mangieri D. Ribatti D. Svelto M. M. Roncali 2004Altered blood-brain barrier development in dystrophic MDX mice. , 125 4 921 935
Nicoletti J. N. Shah S. K. Mc Closkey D. P. Goodman J. H. Elkady A. Atassi H. Hylton D. Rudge J. S. Scharfman H. E. Croll S. D. 2008Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus. . 151 1 232 241
Nies A. T. Jedlitschky G. König J. Herold-Mende C. Steiner H. H. Schmitt H. P. Keppler D. 2004Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. . 129 2 349 360
Nitsch C. Suzuki R. Fujiwara K. Klatzo I. 1985Incongruence of regional cerebral blood flow increase and blood-brain barrier opening in rabbits at the onset of seizures induced by bicuculline, methoxypyridoxine, and kainic acid. , 67 1 67 79
Nitta T. Hata M. Gotoh S. Seo Y. Sasaki H. Hashimoto N. Furuse M. Tsukita S. 2003Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. . 161 3 653 660
Nusrat A. Brown G. T. Tom J. Drake A. Bui T. T. Quan C. Mrsny R. J. 2005Multiple protein interactions involving proposed extracellular loop domains of the tight junction protein occludin. 16 4 1725 1734
Ndode-Ekane X. E. Hayward N. Gröhn O. Pitkänen A. 2010Vascular changes in epilepsy: functional consequences and association with network plasticity in pilocarpine-induced experimental epilepsy. . 166 1 312 332
Oby E. Janigro D. 2006The blood-brain barrier and epilepsy. . 47 11 1761 1774
Ohtsuki S. 2004New aspects of the blood-brain barrier transporters; its physiological roles in the central nervous system. . 27 10 1489 1496
Ohtsuki S. Asaba H. Takanaga H. Deguchi T. Hosoya K. Otagiri M. Terasaki T. 2002Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain, 83 1 57 66
Ohtsuki S. Sato S. Yamaguchi H. Kamoi M. Asashima T. Terasaki T. 2007Exogenous expression of claudin-5 induces barrier properties in cultured rat brain capillary endothelial cells. 210 1 81 86
Ohtsuki S. Takizawa T. Takanaga H. Hori S. Hosoya K. Terasaki T. 2004Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells. , 90 3
Ohtsuki S. Tachikawa M. Takanaga H. Shimizu H. Watanabe M. Hosoya K. Terasaki T. 2002The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. . 22 11 1327 1335
O’Kane R. L. Martínez-López I. De Joseph M. R. Viña J. R. Hawkins R. A. 1999Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. , 274 45 31891 31895
Olivier B. Soudijn W. van Wijngaarden I. 2000Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors. , 54 59 119
Oliveira M. S. Furian A. F. Royes L. F. Fighera M. R. Fiorenza N. G. Castelli M. Machado P. Bohrer D. Veiga M. Ferreira J. Cavalheiro E. A. Mello C. F. 2008Cyclooxygenase-2/PGE2 pathway facilitates pentylenetetrazol-induced seizures, , 79 1 14 21
( Omidi Y. Barar J. Ahmadian S. Heidari H. R. Gumbleton M. 2008). Characterization and astrocytic modulation of system L transporters in brain microvasculature endothelial cells. Cell Biochemistry and Function, Vol. 26, No. 3, .
Ose A. Kusuhara H. Endo C. Tohyama K. Miyajima M. Kitamura S. Sugiyama Y. 2010Functional characterization of mouse organic anion transporting peptide 1a4 in the uptake and efflux of drugs across the blood-brain barrier. . 38 1 168 176
Oztaş B. Kaya M. 1991The effect of acute hypertension on blood-brain barrier permeability to albumin during experimentally induced epileptic seizures. . 23 1 41 46
Pardridge W. M. 2007Blood-brain barrier delivery. . 12 1-2 54 61
Pardridge W. M. Boado R. J. Farrell C. R. 1990Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridization. . 265 29 18035 18040
Piwnica-Worms D. Kesarwala A. H. Pichler A. Prior J. L. Sharma V. 2006Single photon emission computed tomography and positron emission tomography imaging of multi-drug resistant P-glycoprotein--monitoring a transport activity important in cancer, blood-brain barrier function and Alzheimer’s disease. . 16 4 575 589viii.
Ponting C. P. Phillips C. Davies K. E. Blake D. J. 1997PDZ domains: targeting signalling molecules to sub-membranous sites. 19 6
Predescu S. A. Predescu D. N. Malik A. B. 2007Molecular determinants of endothelial transcytosis and their role in endothelial permeability. . 293 4L823-842.
( Quezada C.A. Garrido W.X. González-Oyarzún M.A. Rauch M.C. Salas M.R. San Martín R.E. Claude A.A. Yañez A.J. Slebe J.C. Cárcamo J.G. 2008). Effect of tacrolimus on activity and expression of P-glycoprotein and ATP-binding cassette transporter A5 (ABCA5) proteins in hematoencephalic barrier cells. Biological & Pharmaceutical Bulletin. 10 31 1911 1916
Reichel A. Begley D. J. Ermisch A. 1996Arginine vasopressin reduces the blood-brain transfer of L-tyrosine and L-valine: further evidence of the effect of the peptide on the L-system transporter at the blood-brain barrier. , 713 1-2 232 239
Riazi K. Galic M. A. Kuzmiski J. B. Ho W. Sharkey K. A. Pittman Q. J. 2008Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. , 105 44 17151 17156
( Rigau V. Morin M. Rousset M.C. de Bock F. Lebrun A. Coubes P. Picot M.C. Baldy-Moulinier M. Bockaert J. Crespel A. Lerner-Natoli M. 2007). Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain, 130 1942 1956
Rossi B. Angiari S. Zenaro E. Budui S. L. Constantin G. 2011Vascular inflammation in central nervous system diseases: adhesion receptors controlling leukocyte-endothelial interactions. , 89 4 539 556
Rubin L. L. Staddon J. M. 1999The cell biology of the blood brain barrier. 22 11 28
Ruffer C. Gerke V. 2004The C-terminal cytoplasmic tail of claudins 1 and 5 but not its PDZ-binding motif is required for apical localization at epithelial and endothelial tight junctions. , 83 4
Ruth R. E. 1984Increased cerebrovascular permeability to protein during systemic kainic acid seizures. , 25 2 259 268
Sakaeda T. Siahaan T. J. Audus K. L. Stella V. J. 2000Enhancement of transport of D-melphalan analogue by conjugation with L-glutamate across bovine brain microvessel endothelial cell monolayers. , 8 3 195 204
Seiffert E. Dreier J. P. Ivens S. Bechmann I. Tomkins O. Heinemann U. Friedman A. 2004Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. , 24 36
Sierralta J. Mendoza C. 2004PDZ-containing proteins: alternative splicing as a source of functional diversity. , 47 1-3
Simionescu N. Simionescu M. 1985Interactions of endogenous lipoproteins with capillary endothelium in spontaneously hyperlipoproteinemic rats. . 30 3 314 332
Sinha S. Patil S. A. Jayalekshmy V. Satishchandra P. 2008Do cytokines have any role in epilepsy? , 82 2-3 171 176
Sheen S. H. Kim J. E. Ryu H. J. Yang Y. Choi K. C. Kang T. C. 2011Decrease in dystrophin expression prior to disruption of brain-blood barrier within the rat piriform cortex following status epilepticus. , 1369 173 183
Small V. J. Rottner K. Kaverina I. 1999Functional design in the actin cytoskeleton. 11 54 60
Sobocki T. Sobocka M. B. Babinska A. Ehrlich Y. H. Banerjee P. Kornecki E. 2006Genomic structure, organization and promoter analysis of the human F11R/F11 receptor/junctional adhesion molecule-1/JAM-A. , 366 1 128 144
Soma T. Chiba H. Kato-Mori Y. Wada T. Yamashita T. Kojima T. Sawada N. 2004Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP. 300 1 202 212
Staddon J. M. Rubin L. L. 1996Cell adhesion, cell junctions and the blood-brain barrier. , 6 622 627
Stamatovic S. M. Keep R. F. Kunkel S. L. Andjelkovic A. V. 2003Potential role of MCP-1 in endothelial cell tight junction ‘opening’: signaling via Rho and Rho kinase. , 116 4615 4628
Sternberger N. H. Sternberger L. A. 1987Blood-brain barrier protein recognized by monoclonal antibody. , 84 22 8169 8173
Stewart P. A. Magliocco M. Hayakawa K. Farrell C. L. Del Maestro R. F. Girvin J. Kaufmann J. C. Vinters H. V. Gilbert J. 1987A quantitative analysis of blood-brain barrier ultrastructure in the aging human. . 33 2 270 282
Sugiyama D. Kusuhara H. Lee Y. J. Sugiyama Y. 2003Involvement of multidrug resistance associated protein 1 (Mrp1) in the efflux transport of 17beta estradiol-D-17beta-glucuronide (E217betaG) across the blood-brain barrier. . 20 9 1394 1400
Suzuki A. Ishiyama C. Hashiba K. Shimizu M. Ebnet K. Ohno S. 2002aPKC kinase activity is required for the asymmetric differentiation of the premature junctional complex dur ing epithelial cell polarization. , 115 3565 3573
Tachikawa M. Kasai Y. Yokoyama R. Fujinawa J. Ganapathy V. Terasaki T. Hosoya K. 2009The blood-brain barrier transport and cerebral distribution of guanidinoacetate in rats: involvement of creatine and taurine transporters. . 111 2 499 509
Takanaga H. Ohtsuki S. Hosoya K. Terasaki T. 2001GAT2/BGT-1 as a system responsible for the transport of gamma-aminobutyric acid at the mouse blood-brain barrier. , 21 10 1232 1239
Tao Y. S. Edwards R. A. Tubb B. Wang S. Bryan J. Mc Crea P. D. 1996beta-Catenin associates with the actin-bundling protein fascin in a noncadherin complex. 134 5 1271 1281
( Terai T. Nishimura N. Kanda I. Yasui N. Sasaki T. 2006). JRAB/MICAL-L2 is a junctional Rab13-binding protein mediating the endocytic recycling of occludin. Molecular Biology of the Cell, 5 17 2465 2475
Tetsuka K. Takanaga H. Ohtsuki S. Hosoya K. Terasaki T. 2003The l-isomer-selective transport of aspartic acid is mediated by ASCT2 at the blood-brain barrier. , 87 4 891 901
Tinsley J. M. Blake D. J. Zuellig R. A. Davies K. E. 1994Increasing complexity of the dystrophin-associated protein complex. , 91 18 8307 8013
( Tomkins O. Feintuch A. Benifla M. Cohen A. Friedman A. Shelef I. 2011). Blood-brain barrier breakdown following traumatic brain injury: a possible role in posttraumatic epilepsy. Cardiovascular Psychiatry and Neurology. 2011:765923
Tomkins O. Friedman O. Ivens S. Reiffurth C. Major S. Dreier J. P. Heinemann U. Friedman A. 2007Blood-brain barrier disruption results in delayed functional and structural alterations in the rat neocortex. , 25 2 367 377
Tomkins O. Shelef I. Kaizerman I. Eliushin A. Afawi Z. Misk A. Gidon M. Cohen A. Zumsteg D. Friedman A. J. 2008Blood-brain barrier disruption in post-traumatic epilepsy. , 79 7 774 777
Tzima E. 2006Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response. . 98 2 176 185
Ueno M. 2007Molecular anatomy of the brain endothelial barrier: an overview of the distributional features. . 14 11 1199 1206
Umeki N. Fukasawa Y. Ohtsuki S. Hori S. Watanabe Y. Kohno Y. Terasaki T. 2002mRNA expression and amino acid transport characteristics of cultured human brain microvascular endothelial cells (hBME). , 17 4 367 373
Utepbergenov D. I. Fanning A. S. Anderson J. M. 2006Dimerization of the scaffolding protein ZO-1 through the second PDZ domain. 281 34 24671 24677
Uva L. Librizzi L. Marchi N. Noe F. Bongiovanni R. Vezzani A. Janigro D. de Curtis M. 2008Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability. . 151 1 303 312
van der Sandt I. C. Gaillard P. J. Voorwinden H. H. de Boer A. G. Breimer D. D. 2001P-glycoprotein inhibition leads to enhanced disruptive effects by anti-microtubule cytostatics at the in vitro blood-brain barrier. . 18 5 587 592
van Vliet E. A. da S. Costa Araújo. S. Redeker R. van Schaik E. Aronica J. A. Gorter 2007Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. . 130Pt 2, 521 534
( Vein A.A. 2008). Science and fate: Lina Stern (1878-1968), a neurophysiologist and biochemist. Journal of the History of the Neurosciences, 2 17 195 206
Vemula S. Roder K. E. Yang T. Bhat G. J. Thekkumkara T. J. Abbruscato T. J. 2009A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. , 328 2 487 495
Vezzani A. Balosso S. Maroso M. Zardoni D. Noé F. Ravizza T. 2010ICE/caspase 1 inhibitors and IL-1beta receptor antagonists as potential therapeutics in epilepsy. , 11 1 43 50
Vezzani A. French J. Bartfai T. Baram T. Z. 2011The role of inflammation in epilepsy. , 7 1 31 40
Villegas J. C. Broadwell R. D. 1993Transcytosis of protein through the mammalian cerebral epithelium and endothelium. II. Adsorptive transcytosis of WGA-HRP and the blood-brain and brain-blood barriers. ., 22 2 67 80
Virgintino D. Robertson D. Errede M. Benagiano V. Girolamo F. Maiorano E. Roncali L. Bertossi M. 2002Expression of P-glycoprotein in human cerebral cortex microvessels. , 50 12 1671 1676
Vorbrodt A. W. Dobrogowska D. H. 2004Molecular anatomy of interendothelial junctions in human blood-brain barrier microvessels. , 42 2 67 75
Wakayama K. Ohtsuki S. Takanaga H. Hosoya K. Terasaki T. 2002Localization of norepinephrine and serotonin transporter in mouse brain capillary endothelial cells. , 44 2 173 180
Wang A. J. Pollard T. D. Herman I. M. 1983Actin filaments stress fibers in vascular endothelial cells in vivo. 219 867 869
Warren M. S. Zerangue N. Woodford K. Roberts L. M. Tate E. H. Feng B. Li C. Feuerstein T. J. Gibbs J. Smith B. de Morais S. M. Dower W. J. Koller K. J. 2009Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. , 59 6 404 413
Williams K. Alvarez X. Lackner A. A. 2001Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. , 36 2 156 164
Williams L. A. Martin-Padura I. Dejana E. Hogg N. Simmons D. L. 1999Identification and characterisation of human Junctional Adhesion Molecule (JAM). . 36 17 1175 1188
Wolburg H. Noell S. Mack A. Wolburg-Buchholz K. Fallier-Becker P. 2009Brain endothelial cells and the glio-vascular complex. . 335 1 75 96
Yamanaka T. Horikoshi Y. Suzuki A. Sugiyama Y. Kitamura K. Maniwa R. Nagai Y. Yamashita A. Hirose T. Ishikawa H. Ohno S. 2001PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex, 6 8 721 731
Yu X. Q. Xue C. C. Wang G. Zhou S. F. 2007Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs. . 8 8 787 802
Xiang J. Ennis S. R. Abdelkarim G. E. Fujisawa M. Kawai N. Keep R. F. 2003Glutamine transport at the blood-brain and blood-cerebrospinal fluid barriers. , 43 4-5 279 288
Zattoni M. Mura M. L. Deprez F. Schwendener R. A. Engelhardt B. Frei K. Fritschy J. M. 2011Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. . 31 11 4037 4050
Zhang Y. Han H. Elmquist W. F. Miller D. W. 2000Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. , 876 1-2 148 153
Zhang W. Mojsilovic-Petrovic J. Andrade M.F. Zhang H. Ball M. Stanimirovic D.B. 2003). The expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB Journal 14 17 2085 2087