Journal articles: 'Adhesion and Invasion of the blood brain barrier'

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Herold, Schroten, and Schwerk. "Virulence Factors of Meningitis-Causing Bacteria: Enabling Brain Entry across the Blood–Brain Barrier." International Journal of Molecular Sciences 20, no. 21 (October 29, 2019): 5393. http://dx.doi.org/10.3390/ijms20215393.

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Infections of the central nervous system (CNS) are still a major cause of morbidity and mortality worldwide. Traversal of the barriers protecting the brain by pathogens is a prerequisite for the development of meningitis. Bacteria have developed a variety of different strategies to cross these barriers and reach the CNS. To this end, they use a variety of different virulence factors that enable them to attach to and traverse these barriers. These virulence factors mediate adhesion to and invasion into host cells, intracellular survival, induction of host cell signaling and inflammatory response, and affect barrier function. While some of these mechanisms differ, others are shared by multiple pathogens. Further understanding of these processes, with special emphasis on the difference between the blood–brain barrier and the blood–cerebrospinal fluid barrier, as well as virulence factors used by the pathogens, is still needed.

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Wegele, Christian, Carolin Stump-Guthier, Selina Moroniak, Christel Weiss, Manfred Rohde, Hiroshi Ishikawa, Horst Schroten, Christian Schwerk, Michael Karremann, and Julia Borkowski. "Non-Typeable Haemophilus influenzae Invade Choroid Plexus Epithelial Cells in a Polar Fashion." International Journal of Molecular Sciences 21, no. 16 (August 10, 2020): 5739. http://dx.doi.org/10.3390/ijms21165739.

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Non-typeable Haemophilus influenzae (NTHI) is a pathogen of the human respiratory tract causing the majority of invasive H. influenzae infections. Severe invasive infections such as septicemia and meningitis occur rarely, but the lack of a protecting vaccine and the increasing antibiotic resistance of NTHI impede treatment and emphasize its relevance as a potential meningitis causing pathogen. Meningitis results from pathogens crossing blood–brain barriers and invading the immune privileged central nervous system (CNS). In this study, we addressed the potential of NTHI to enter the brain by invading cells of the choroid plexus (CP) prior to meningeal inflammation to enlighten NTHI pathophysiological mechanisms. A cell culture model of human CP epithelial cells, which form the blood–cerebrospinal fluid barrier (BCSFB) in vivo, was used to analyze adhesion and invasion by immunofluorescence and electron microscopy. NTHI invade CP cells in vitro in a polar fashion from the blood-facing side. Furthermore, NTHI invasion rates are increased compared to encapsulated HiB and HiF strains. Fimbriae occurrence attenuated adhesion and invasion. Thus, our findings underline the role of the BCSFB as a potential entry port for NTHI into the brain and provide strong evidence for a function of the CP during NTHI invasion into the CNS during the course of meningitis.

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Iovino, Federico, Grietje Molema, and Jetta J. E. Bijlsma. "Platelet Endothelial Cell Adhesion Molecule-1, a Putative Receptor for the Adhesion of Streptococcus pneumoniae to the Vascular Endothelium of the Blood-Brain Barrier." Infection and Immunity 82, no. 9 (June 9, 2014): 3555–66. http://dx.doi.org/10.1128/iai.00046-14.

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ABSTRACTThe Gram-positive bacteriumStreptococcus pneumoniaeis the main causative agent of bacterial meningitis.S. pneumoniaeis thought to invade the central nervous system via the bloodstream by crossing the vascular endothelium of the blood-brain barrier. The exact mechanism by which pneumococci cross endothelial cell barriers before meningitis develops is unknown. Here, we investigated the role of PECAM-1/CD31, one of the major endothelial cell adhesion molecules, inS. pneumoniaeadhesion to vascular endothelium of the blood-brain barrier. Mice were intravenously infected with pneumococci and sacrificed at various time points to represent stages preceding meningitis. Immunofluorescent analysis of brain tissue of infected mice showed that pneumococci colocalized with PECAM-1. In human brain microvascular endothelial cells (HBMEC) incubated withS. pneumoniae, we observed a clear colocalization between PECAM-1 and pneumococci. Blocking of PECAM-1 reduced the adhesion ofS. pneumoniaeto endothelial cellsin vitro, implying that PECAM-1 is involved in pneumococcal adhesion to the cells. Furthermore, using endothelial cell protein lysates, we demonstrated thatS. pneumoniaephysically binds to PECAM-1. Moreover, bothin vitroandin vivoPECAM-1 colocalizes with theS. pneumoniaeadhesion receptor pIgR. Lastly, immunoprecipitation experiments revealed that PECAM-1 can physically interact with pIgR. In summary, we show for the first time that blood-borneS. pneumoniaecolocalizes with PECAM-1 expressed by brain microvascular endothelium and that, in addition, they colocalize with pIgR. We hypothesize that this interaction plays a role in pneumococcal binding to the blood-brain barrier vasculature prior to invasion into the brain.

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Reddy, Marpadga A., Carol A. Wass, Kwang Sik Kim, David D. Schlaepfer, and Nemani V. Prasadarao. "Involvement of Focal Adhesion Kinase inEscherichia coli Invasion of Human Brain Microvascular Endothelial Cells." Infection and Immunity 68, no. 11 (November 1, 2000): 6423–30. http://dx.doi.org/10.1128/iai.68.11.6423-6430.2000.

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ABSTRACT Escherichia coli K1 traversal across the blood-brain barrier is an essential step in the pathogenesis of neonatal meningitis. We have previously shown that invasive E. colipromotes the actin rearrangement of brain microvascular endothelial cells (BMEC), which constitute a lining of the blood-brain barrier, for invasion. However, signal transduction mechanisms involved in E. coli invasion are not defined. In this report we show that tyrosine kinases play a major role in E. coli invasion of human BMEC (HBMEC). E. coli induced tyrosine phosphorylation of HBMEC cytoskeletal proteins, focal adhesion kinase (FAK), and paxillin, with a concomitant increase in the association of paxillin with FAK. Overexpression of a dominant interfering form of the FAK C-terminal domain, FRNK (FAK-related nonkinase), significantly inhibited E. coli invasion of HBMEC. Furthermore, we found that FAK kinase activity and the autophosphorylation site (Tyr397) are important in E. coli invasion of HBMEC, whereas the Grb2 binding site (Tyr925) is not required. Immunocytochemical studies demonstrated that FAK is recruited to focal plaques at the site of bacterial entry. Consistent with the invasion results, overexpression of FRNK, a kinase-negative mutant (Arg454 FAK), and a Src binding mutant (Phe397 FAK) inhibited the accumulation of FAK at the bacterial entry site. The overexpression of FAK mutants in HBMEC also blocked theE. coli-induced tyrosine phosphorylation of FAK and its association with paxillin. These observations provide evidence that FAK tyrosine phosphorylation and its recruitment to the cytoskeleton play a key role in E. coli invasion of HBMEC.

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Iovino, Federico, Joo-Yeon Engelen-Lee, Matthijs Brouwer, Diederik van de Beek, Arie van der Ende, Merche Valls Seron, Peter Mellroth, et al. "pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion." Journal of Experimental Medicine 214, no. 6 (May 17, 2017): 1619–30. http://dx.doi.org/10.1084/jem.20161668.

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Streptococcus pneumoniae is the main cause of bacterial meningitis, a life-threating disease with a high case fatality rate despite treatment with antibiotics. Pneumococci cause meningitis by invading the blood and penetrating the blood–brain barrier (BBB). Using stimulated emission depletion (STED) super-resolution microscopy of brain biopsies from patients who died of pneumococcal meningitis, we observe that pneumococci colocalize with the two BBB endothelial receptors: polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1). We show that the major adhesin of the pneumococcal pilus-1, RrgA, binds both receptors, whereas the choline binding protein PspC binds, but to a lower extent, only pIgR. Using a bacteremia-derived meningitis model and mutant mice, as well as antibodies against the two receptors, we prevent pneumococcal entry into the brain and meningitis development. By adding antibodies to antibiotic (ceftriaxone)-treated mice, we further reduce the bacterial burden in the brain. Our data suggest that inhibition of pIgR and PECAM-1 has the potential to prevent pneumococcal meningitis.

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Matin, Abdul, Ruqaiyyah Siddiqui, Suk-Yul Jung, Kwang Sik Kim, Monique Stins, and Naveed Ahmed Khan. "Balamuthia mandrillaris interactions with human brain microvascular endothelial cells in vitro." Journal of Medical Microbiology 56, no. 8 (August 1, 2007): 1110–15. http://dx.doi.org/10.1099/jmm.0.47134-0.

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Balamuthia amoebic encephalitis (BAE) is a serious human disease almost always leading to death. An important step in BAE is amoebae invasion of the bloodstream, followed by their haematogenous spread. Balamuthia mandrillaris entry into the central nervous system most likely occurs at the blood–brain barrier sites. Using human brain microvascular endothelial cells (HBMECs), which constitute the blood–brain barrier, this study determined (i) the ability of B. mandrillaris to bind to HBMECs and (ii) the associated molecular mechanisms. Adhesion assays revealed that B. mandrillaris exhibited greater than 90 % binding to HBMECs in vitro. To determine whether recognition of carbohydrate moieties on the surface of the HBMECs plays a role in B. mandrillaris adherence to the target cells, adhesion assays were performed in the presence of the saccharides mannose, galactose, xylose, glucose and fucose. It was observed that adherence of B. mandrillaris was significantly reduced by galactose, whilst the other saccharides had no effect. Acetone fixation of amoebae, but not of HBMECs, abolished adhesion, suggesting that B. mandrillaris adhesin(s) bind to galactose-containing glycoproteins of HBMECs. B. mandrillaris also bound to microtitre wells coated with galactose–BSA. By affinity chromatography using a galactose–Sepharose column, a galactose-binding protein (GBP) was isolated from detergent extracts of unlabelled amoebae. The isolation of a GBP from cell-surface-biotin-labelled amoebae suggested its membrane association. One-dimensional SDS-PAGE confirmed the proteinaceous nature of the GBP and determined its molecular mass as approximately 100 kDa. This is the first report suggesting the role of a GBP in B. mandrillaris interactions with HBMECs.

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Masocha, Willias, Martin E. Rottenberg, and Krister Kristensson. "Minocycline Impedes African Trypanosome Invasion of the Brain in a Murine Model." Antimicrobial Agents and Chemotherapy 50, no. 5 (May 2006): 1798–804. http://dx.doi.org/10.1128/aac.50.5.1798-1804.2006.

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ABSTRACT Passage of Trypanosoma brucei across the blood-brain barrier (BBB) is a hallmark of late-stage human African trypanosomiasis. In the present study we found that daily administration of minocycline, a tetracycline antibiotic, impedes the penetration of leukocytes and trypanosomes into the brain parenchyma of T. brucei brucei-infected C57BL/6 mice. The trypanosome-induced astrocytic and microglial reactions were reduced in the minocycline-treated mice, as were the levels in the brain of transcripts encoding adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and endothelial-leukocyte adhesion molecule 1 (E-selectin); the inflammatory cytokines tumor necrosis factor alpha, interleukin-1α (IL-1α), IL-1β, IL-6, and gamma interferon; and matrix metalloprotease 3 (MMP-3), MMP-8, and MMP-12. Loss of weight occurring during infection with T. b. brucei was not observed after treatment of the mice with minocycline; these mice also survived longer than nontreated mice. Invasion of trypanosomes and leukocytes into the brain parenchyma most likely triggered the loss of weight and death of infected animals, since minocycline did not affect the growth of T. b. brucei either in vitro or in vivo or the levels of the transcripts encoding the cytokines and MMPs in the spleen. In conclusion, our data show that T. b. brucei invasion of the brain is related to that of leukocytes and that minocycline can ameliorate the disease in trypanosome-infected mice.

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Hertzig, Tobias, Martin Weber, Lars Greiffenberg, Britta Schulte Holthausen, Werner Goebel, Kwang Sik Kim, and Michael Kuhn. "Antibodies Present in Normal Human Serum Inhibit Invasion of Human Brain Microvascular Endothelial Cells by Listeria monocytogenes." Infection and Immunity 71, no. 1 (January 2003): 95–100. http://dx.doi.org/10.1128/iai.71.1.95-100.2003.

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ABSTRACT Listeria monocytogenes causes meningitis and encephalitis in humans and crosses the blood-brain barrier by yet unknown mechanisms. The interaction of the bacteria with different types of endothelial cells was recently analyzed, and it was shown that invasion into, but not adhesion to, human brain microvascular endothelial cells (HBMEC) depends on the product of the inlB gene, the surface molecule InlB, which is a member of the internalin multigene family. In the present study we analyzed the role of the medium composition in the interaction of L. monocytogenes with HBMEC, and we show that invasion of HBMEC is strongly inhibited in the presence of adult human serum. The strong inhibitory activity, which is not present in fetal calf serum, does not inhibit uptake by macrophage-like J774 cells but does also inhibit invasion of Caco-2 epithelial cells. The inhibitory component of human serum was identified as being associated with L. monocytogenes-specific antibodies present in the human serum. Human newborn serum (cord serum) shows only a weak inhibitory activity on the invasion of HBMEC by L. monocytogenes.

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Rizzo, A., C. Vasco, V. Girgenti, V. Fugnanesi, C. Calatozzolo, A. Canazza, A. Salmaggi, L. Rivoltini, M. Morbin, and E. Ciusani. "Melanoma Cells Homing to the Brain: AnIn VitroModel." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/476069.

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We developed anin vitrocontact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 μm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across thein vitroBBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM,αvβ3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion.

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Vanier, Ghyslaine, Anna Szczotka, Peter Friedl, Sonia Lacouture, Mario Jacques, and Marcelo Gottschalk. "Haemophilus parasuis invades porcine brain microvascular endothelial cells." Microbiology 152, no. 1 (January 1, 2006): 135–42. http://dx.doi.org/10.1099/mic.0.28312-0.

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Haemophilus parasuis, an important swine pathogen, is the aetiological agent of Glässer's disease. It is responsible for cases of polyserositis, meningitis and pneumonia in young pigs. To date, 15 serotypes have been described, although several non-typable isolates are frequently recovered from diseased animals. The pathogenesis of H. parasuis infection is poorly understood. To cause meningitis, H. parasuis would have to cross the blood–brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC). The objective of this study was to investigate the ability of H. parasuis to interact with porcine brain microvascular endothelial cells (PBMEC). It was demonstrated that the serotype 5 reference strain of H. parasuis, Nagasaki (originally recovered from a case of meningitis), was able to adhere at very high levels to and, most importantly, invade PBMEC. These capacities were confirmed by electron microscopy. Actinobacillus pleuropnemoniae serotype 7 (strain WF 83), used as negative control, was not able to adhere to or invade PBMEC. Comparisons of the levels of adhesion and invasion by several H. parasuis field strains from different serotypes isolated from cases of either meningitis or pneumonia showed that isolates of serotypes 4 and 5 had a higher invasion capacity than isolates belonging to other serotypes. Inhibition studies demonstrated that PBMEC invasion by H. parasuis required rearrangement of actin microfilaments and microtubular cytoskeletal elements but not active bacterial DNA, RNA or protein synthesis. Characterization studies demonstrated that proteinaceous invasin(s) does not seem to play a major role in entry of H. parasuis into PBMEC. Intracellular viable H. parasuis were found in PBMEC up to 6 h after antibiotic treatment. Even at high bacterial doses, H. parasuis was not toxic to PBMEC. In swine, the invasion of endothelial cells of the BBB may play an important role in the pathogenesis of meningitis caused by H. parasuis.

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Vanier, Ghyslaine, Mariela Segura, Peter Friedl, Sonia Lacouture, and Marcelo Gottschalk. "Invasion of Porcine Brain Microvascular Endothelial Cells by Streptococcus suis Serotype 2." Infection and Immunity 72, no. 3 (March 2004): 1441–49. http://dx.doi.org/10.1128/iai.72.3.1441-1449.2004.

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ABSTRACT Streptococcus suis is an important swine pathogen that mainly causes meningitis and occasionally causes other infections, such as endocarditis, arthritis, and pneumonia. The pathogenesis of S. suis infection has not been completely defined. However, in order to cause meningitis, S. suis has to cross the blood-brain barrier (BBB) made up of brain microvascular endothelial cells. The objective of this work was to study the interactions of S. suis serotype 2 with porcine brain microvascular endothelial cells (PBMEC). The ability of North American and European S. suis serotype 2 strains to adhere to PBMEC and, most importantly, to invade PBMEC was demonstrated by using an antibiotic protection assay and was confirmed by electron microscopy. The polysaccharide capsule of S. suis seemed to partially interfere with the adhesion and invasion abilities of the bacterium. Our results showed that intracellular viable S. suis could be found in PBMEC up to 7 h after antibiotic treatment. Inhibition studies demonstrated that invasion of PBMEC by S. suis required actin microfilaments but not microtubular cytoskeletal elements or active bacterial RNA or protein synthesis. At high bacterial doses, suilysin-positive strains were toxic for PBMEC. The role of suilysin in cytotoxicity was confirmed by using purified suilysin, electron microscopy, and the lack of toxicity of a suilysin-negative mutant. In swine, the invasion of endothelial cells of the BBB could play an important role in the pathogenesis of the meningitis caused by S. suis.

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Göbel, Kerstin, Chloi-Magdalini Asaridou, Monika Merker, Susann Eichler, Alexander M. Herrmann, Eva Geuß, Tobias Ruck, et al. "Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release." Proceedings of the National Academy of Sciences 116, no. 1 (December 17, 2018): 271–76. http://dx.doi.org/10.1073/pnas.1810020116.

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Blood–brain barrier (BBB) disruption and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of neuroinflammatory disorders like multiple sclerosis (MS). Recent evidence suggests that the kallikrein-kinin and coagulation system might participate in this process. Here, we identify plasma kallikrein (KK) as a specific direct modulator of BBB integrity. Levels of plasma prekallikrein (PK), the precursor of KK, were markedly enhanced in active CNS lesions of MS patients. Deficiency or pharmacologic blockade of PK renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by a remarkable reduction of BBB disruption and CNS inflammation. In vitro analysis revealed that KK modulates endothelial cell function in a protease-activated receptor-2–dependent manner, leading to an up-regulation of the cellular adhesion molecules Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1, thereby amplifying leukocyte trafficking. Our study demonstrates that PK is an important direct regulator of BBB integrity as a result of its protease function. Therefore, KK inhibition can decrease BBB damage and cell invasion during neuroinflammation and may offer a strategy for the treatment of MS.

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Ebrahimi, Celia M., Justin W. Kern, Tamsin R. Sheen, Mohammad A. Ebrahimi-Fardooee, Nina M. van Sorge, Olaf Schneewind, and Kelly S. Doran. "Penetration of the Blood-Brain Barrier by Bacillus anthracis Requires the pXO1-Encoded BslA Protein." Journal of Bacteriology 191, no. 23 (October 9, 2009): 7165–73. http://dx.doi.org/10.1128/jb.00903-09.

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ABSTRACT Anthrax is a zoonotic disease caused by the gram-positive spore-forming bacterium Bacillus anthracis. Human infection occurs after the ingestion, inhalation, or cutaneous inoculation of B. anthracis spores. The subsequent progression of the disease is largely mediated by two native virulence plasmids, pXO1 and pXO2, and is characterized by septicemia, toxemia, and meningitis. In order to produce meningitis, blood-borne bacteria must interact with and breach the blood-brain barrier (BBB) that is composed of a specialized layer of brain microvascular endothelial cells (BMEC). We have recently shown that B. anthracis Sterne is capable of penetrating the BBB in vitro and in vivo, establishing the classic signs of meningitis; however, the molecular mechanisms underlying the central nervous system (CNS) tropism are not known. Here, we show that attachment to and invasion of human BMEC by B. anthracis Sterne is mediated by the pXO1 plasmid and an encoded envelope factor, BslA. The results of studies using complementation analysis, recombinant BslA protein, and heterologous expression demonstrate that BslA is both necessary and sufficient to promote adherence to brain endothelium. Furthermore, mice injected with the BslA-deficient strain exhibited a significant decrease in the frequency of brain infection compared to mice injected with the parental strain. In addition, BslA contributed to BBB breakdown by disrupting tight junction protein ZO-1. Our results identify the pXO1-encoded BslA adhesin as a critical mediator of CNS entry and offer new insights into the pathogenesis of anthrax meningitis.

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Nešović, Marija, Aleksandra Divac Rankov, Ana Podolski-Renić, Igor Nikolić, Goran Tasić, Arianna Mancini, Silvia Schenone, Milica Pešić, and Jelena Dinić. "Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo." Cancers 12, no. 6 (June 14, 2020): 1570. http://dx.doi.org/10.3390/cancers12061570.

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Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood–brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.

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Michiue, Hiroyuki, Nobushige Tsuboi, Keiichiro Hayashi, Hideki Matsui, and Kazuhiko Kurozumi. "DDIS-01. NEW DRUG DISCOVERY WITH DRUG RE-POSITIONING SYSTEM TOWARD GBM TREATMENT." Neuro-Oncology 21, Supplement_6 (November 2019): vi65. http://dx.doi.org/10.1093/neuonc/noz175.261.

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Abstract INTRODUCTION Invasion of Glioblastoma (GBM) cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM cells. Therefore, we hypothesized that the inhibition of actin polymerization with existing medication could lead to clinical GBM treatment directly in short time. The Drug Repositioning system is also known as drug repurposing or drug reprofiling and understood as the process of redeveloping a compound for use in a different disease. In this time, we would show the new direction of drug development with drug repositioning. MATERIALS AND METHODS We adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood–brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. RESULTS Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing FAK signaling. Fluvoxamine showed no drug toxicity. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same doze of anti-depressant effect. CONCLUSIONS The SSRI group has big potential for clinical GBM treatment with low cost, short time and low side effect.

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Poglio, Sandrine, Anne-Laure Bauchet, José Ramon Pineda, Caroline Deswarte, Thierry Leblanc, André Baruchel, Paola Ballerini, et al. "New Design Of Human T-ALL Transplantation In NSG Mice Uncovers The Major Role Of CD31/PECAM1 In The Central Nervous System Infiltration." Blood 122, no. 21 (November 15, 2013): 1436. http://dx.doi.org/10.1182/blood.v122.21.1436.1436.

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Abstract T-cell acute lymphoblastic leukemia (T-ALL) is mainly a child and adolescent blood malignancy. T-ALL patients present an increased risk of Central Nervous System (CNS) relapse defined by leukemic cell infiltration in cerebrospinal fluid and brain. Using transgenic mice and T-ALL cell lines previous works have shown that T-ALL migration in CNS depends on CCR7 chemokine receptor expression (S. Buonamici et al., Nature, 2009). VE-cadherin and CD31/PECAM1 also seem implicated, as it has been shown in vitro (S. M. Akers et al., Exp Hematol, 2010). In patients, high level of IL-15 at diagnosis predicts current CNS invasion and sometimes at relapse (G. Cario et al., J Clin Oncol, 2007). So far no study has investigated mechanisms involved in CNS infiltration using T-ALL patient samples in vivo. In the present study we developed a mouse model of CNS infiltration using leukemic cells isolated from patients and transplanted into NOD/SCID IL2Rуc-/- (NSG) mice. Proper conditioning of NSG mice and different routes of injection were tested to define a protocol avoiding non-specific CNS infiltration of leukemic cells. Also bone marrow (BM) engraftment levels of leukemia between 60 to 100% were used to set up the excision time of hematopoietic tissues and brain. Leukemic blasts from 8 patients with or 9 patients without CNS invasion were grafted and brain infiltration was followed up using standard histology and immunohistochemistry techniques. Our data indicate that (1) under specific experimental procedures, leukemic cells from patients with CNS invasion did infiltrate mouse CNS (8/8 samples) whereas the majority of cells from “non-infiltrated” patients did not (7/9 samples), (2) leukemic cells recovered from NSG brain and BM were similar in terms of brain and/or BM infiltration in secondary transplant experiments. Moreover, T-Leukemia Initiating Cell frequency was the same whatever the BM or CNS origin of blasts in the primary recipient. Interestingly, analysis of blasts at diagnosis showed that surface expression of adhesion molecules can not discriminate CNS+ or CNS- leukemic cells. However, blocking of CD31 decreased in vitro migration of blasts from CNS+ compared to CNS- patients through endothelial layer derived from blood brain barrier cells. Pioneered in vivo experiments show that CNS+ blasts pre-treated with CD31 antibody and injected in NSG are less prone to colonize mouse brain. Moreover, knocking down CD31 in CNS+ T-ALL by lentiviral shRNA strategy impairs leukemia development in mice, further decreasing CNS infiltration, whatever injection routes is used including intrafemoral injection. In conclusion, T-ALL xenografts in NSG mice mimic CNS invasion in patients. CD31 is a major player in blast cells migration in vitro and brain infiltration in vivo. This new model opens a new area of investigation to improve our knowledge of the molecular mechanisms of CNS infiltration in T-ALL. Disclosures: No relevant conflicts of interest to declare.

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Hayden, Melvin, DeAna Grant, Annayya Aroor, and Vincent DeMarco. "Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model–Part II: Microglia and Mitochondria." Neuroglia 1, no. 2 (October 7, 2018): 311–26. http://dx.doi.org/10.3390/neuroglia1020021.

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Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. This study tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions may depict abnormal cellular remodeling. The monogenic (Leprdb) female diabetic db/db [BKS.CgDock7m +/+Leprdb/J] (DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (20 weeks), left-brain hemispheres of the DBC and age-matched nondiabetic control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We observed an attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickened basement membranes, adherent red and white blood cells, neurovascular unit microbleeds and pathologic remodeling of protoplasmic astrocytes. In this second of a three-part series, we focus on the observational ultrastructural remodeling of microglia and mitochondria in relation to the NVU in leptin receptor deficient DBC models. This study identified novel ultrastructural core signature remodeling changes, which consisted of invasive activated microglia, microglial aberrant mitochondria with nuclear chromatin condensation and adhesion of white blood cells to an activated endothelium of the NVU. In conclusion, the results implicate activated microglia in NVU uncoupling and the resulting ischemic neuronal and synaptic damage, which may be related to impaired cognition and diabetic cognopathy.

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Immidisetti, Amanda, Chibueze Nwagwu, W. Shawn Carbonell, and Anne-Marie Carbonell. "ACTR-55. OPTIMIZED TREAT-RESECT-TREAT STUDY DESIGN FOR CONVECTION-ENHANCED DELIVERY OF A FIRST-IN-CLASS BIOLOGIC IN THE TREATMENT OF GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi26. http://dx.doi.org/10.1093/neuonc/noz175.097.

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Abstract INTRODUCTION Development of effective treatments for high-grade glioma (HGG) including glioblastoma is hampered by 1) the blood brain barrier, 2) an infiltrative growth pattern, 3) rapid development of adaptive therapeutic resistance, and 4) dose-limiting toxicity due to systemic exposure. Novel therapeutics and delivery techniques are warranted to overcome these obstacles and meaningfully improve patient outcomes. OS2966 is the first ever clinical-ready therapeutic candidate against the adhesion receptor subunit, CD29/β1 integrin. CD29 is highly overexpressed in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy including immunotherapies. Here, we present a novel phase I trial design addressing all four obstacles plaguing effective treatment of HGG, while also enabling biomarker development. STUDY DESIGN This 2-part, ascending concentration, phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically-indicated resection. In part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which is used for intratumoral convection-enhanced delivery (CED) of OS2966. Subsequently, patients undergo their clinically-indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched, pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. DISCUSSION The present study design leverages multiple innovations including: 1) the latest CED technology, 2) two-part design including neoadjuvant intratumoral administration, 3) a first-in-class investigational therapeutic, and 4) concentration-based dosing. A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.

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Goswami, Surbhi, Shubham Parashar, Vandita Dwivedi, Asif Shajahan, and Srinivasa-Gopalan Sampathkumar. "Chemical and biological methods for probing the structure and functions of polysialic acids." Emerging Topics in Life Sciences 2, no. 3 (September 11, 2018): 363–76. http://dx.doi.org/10.1042/etls20180008.

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Owing to its poly-anionic charge and large hydrodynamic volume, polysialic acid (polySia) attached to neural cell adhesion molecule regulates axon–axon and axon–substratum interactions and signalling, particularly, in the development of the central nervous system (CNS). Expression of polySia is spatiotemporally regulated by the action of two polysialyl transferases, namely ST8SiaII and ST8SiaIV. PolySia expression peaks during late embryonic and early post-natal period and maintained at a steady state in adulthood in neurogenic niche of the brain. Aberrant polySia expression is associated with neurological disorders and brain tumours. Investigations on the structure and functions, over the past four decades, have shed light on the physiology of polySia. This review focuses on the biological, biochemical, and chemical tools available for polySia engineering. Genetic knockouts, endo-neuraminidases that cleave polySia, antibodies, exogenous expression, and neuroblastoma cells have provided deep insights into the ability of polySia to guide migration of neuronal precursors in neonatal brain development, neuronal clustering, axonal pathway guidance, and axonal targeting. Advent of metabolic sialic acid engineering using ManNAc analogues has enabled reversible and dose-dependent modulation polySia in vitro and ex vivo. In vivo, ManNAc analogues readily engineer the sialoglycans in peripheral tissues, but show no effect in the brain. A recently developed carbohydrate-neuroactive hybrid strategy enables a non-invasive access to the brain in living animals across the blood–brain barrier. A combination of recent advances in CNS drugs and imaging with ManNAc analogues for polySia modulation would pave novel avenues for understanding intricacies of brain development and tackling the challenges of neurological disorders.

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Lassmann, H. "Blood-brain barrier and adhesion molecules." Journal of Neuroimmunology 54, no. 1-2 (October 1994): 175. http://dx.doi.org/10.1016/0165-5728(94)90401-4.

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Yang, Xue, Dapeng Wu, and Shengli Yuan. "Tyrosine Kinase Inhibitors in the Combination Therapy of HER2 Positive Breast Cancer." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382096214. http://dx.doi.org/10.1177/1533033820962140.

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Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) accounts for about 20% to 30% of all BC subtypes and is characterized by invasive disease and poor prognosis. With the emergence of anti-HER2 target drugs, HER2-positive BC patient outcomes have changed dramatically. However, treatment failure is mostly due to drug resistance and the special treatment needs of different subgroups. Small molecule tyrosine kinase inhibitors can inhibit multiple targets of the human epidermal growth factor receptor family and activate PI3K/AKT, MAPK, PLC γ, ERK1/2, JAK/STAT, and other pathways affecting the expression of MDM2, mTOR, p27, and other transcription factors. This can help regulate the differentiation, apoptosis, migration, growth, and adhesion of normal cells and reverse drug resistance to a certain extent. These inhibitors can cross the blood-brain barrier and be administered orally. They have a good synergistic effect with effective drugs such as trastuzumab, pertuzumab, t-dm1, and cyclin-dependent kinase 4 and 6 inhibitors. These advantages have resulted in small-molecule tyrosine kinase inhibitors attracting attention. The new small-molecule tyrosine kinase inhibitor was investigated in multi-target anti-HER2 therapy, showed a good effect in preclinical and clinical trials, and to some extent, improved the prognosis of HER2-positive BC patients. Its use could lead to a de-escalation of treatment in some patients, possibly preventing unnecessary procedures along with the associated side effects and costs.

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Jackson, Hannah K., Franziska Linke, Ian Kerr, and Beth Coyle. "MBRS-27. EXOSOMES CARRY DISTINCT miRNAs THAT DRIVE MEDULLOBLASTOMA PROGRESSION." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii403. http://dx.doi.org/10.1093/neuonc/noaa222.542.

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Abstract INTRODUCTION Extracellular vesicles (EVs) represent an ideal source of functional biomarkers due to their role in intercellular communication and their ability to protect cargo, including RNA, from degradation. The most investigated EV’s are exosomes, nanovesicles secreted by all cell types and able to cross the blood-brain-barrier. Here we characterised the RNA of exosomes isolated from medulloblastoma cell lines, with the aim of investigating exosomal RNA cargo as potential functional biomarkers for medulloblastoma. METHODS Exosomes derived from a panel of matched (original tumour and metastasis) medulloblastoma cell lines were isolated and characterised by NanoSight, electron microscopy, western blotting and Nanoscale flow cytometry. Exosomal miRNA and mRNA from our matched cell lines and foetal neuronal stem cells, which were used as a normal control, were analysed by RNA-sequencing technology. RESULTS Based on hierarchical clustering, malignant derived exosomes were distinctly separated from normal control exosomes. miRNA profiling revealed several established oncomiRs identified in our malignant derived exosomes compared to control samples. Using interaction pathway analysis, we identified that our malignant exosomes carry numerous miRNAs implicated in migration, proliferation, cellular adhesion and tumour growth. Several previously identified oncomiRs were also identified to be present at higher levels in metastatic exosomes compared to primary and normal, including hsa-miR-455-3p and hsa-miR-92a-3p. CONCLUSION This study shows that exosomes from MB cells carry a distinct miRNA cargo which could enhance medulloblastoma progression. The use of circulating exosomes as markers of metastatic disease could be an innovative and powerful non-invasive tool.

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Lassmann, H. "Blood-brain-barrier and cell adhesion molecules." Journal of Neuroimmunology 56-63 (1995): 11. http://dx.doi.org/10.1016/0165-5728(95)98885-f.

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Lassmann, H. "Adhesion molecules of the blood-brain barrier." Journal of Neuroimmunology 43, no. 1-2 (March 1993): 208–9. http://dx.doi.org/10.1016/0165-5728(93)90115-f.

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del Zoppo, G. J., R. Milner, T. Mabuchi, S. Hung, X. Wang, and J. A. Koziol. "Vascular matrix adhesion and the blood–brain barrier." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1261–66. http://dx.doi.org/10.1042/bst0341261.

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The integrity of the cerebral microvasculature depends on the interaction between its component cells and the extracellular matrix, as well as reorganized cell–cell interactions. In the central nervous system, matrix adhesion receptors are expressed in the microvasculature and by neurons and their supporting glial cells. Cells within cerebral microvessels express both the integrin and dystroglycan families of matrix adhesion receptors. However, the functional significance of these receptors is only now being explored. Endothelial cells and astrocytes within cerebral capillaries co-operate to generate and maintain the basal lamina and the unique barrier functions of the endothelium. Integrins and the dystroglycan complex are found on the matrix-proximate faces of both endothelial cells and astrocyte end-feet. Pericytes rest against the basal lamina. In the extravascular compartment, select integrins are expressed on neurons, microglial cells and oligodendroglia. Significant alterations in both cellular adhesion receptors and their matrix ligands occur during focal cerebral ischaemia, which support their functional significance in the normal state. We propose that matrix adhesion receptors are essential for the maintenance of the integrity of the blood–brain permeability barrier and that modulation of these receptors contributes to alterations in the barrier during brain injury.

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Staddon, James M., and Lee L. Rubin. "Cell adhesion, cell junctions and the blood—brain barrier." Current Opinion in Neurobiology 6, no. 5 (October 1996): 622–27. http://dx.doi.org/10.1016/s0959-4388(96)80094-8.

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Minagar, Alireza, and J. Steven Alexander. "Blood-brain barrier disruption in multiple sclerosis." Multiple Sclerosis Journal 9, no. 6 (December 2003): 540–49. http://dx.doi.org/10.1191/1352458503ms965oa.

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The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (C EC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. C ollectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the ‘interior milieu’ of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal C NS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendo thelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/chemokines on endothelial regulation of BBB components, as well as indirect cytokine/chemokine-dependent leukocyte mediated injury. Unique endothelial structural features of the BBB include highly organized endothelial tight junctions, the absence of class II major histocompatibility complex, abundant mitochondria and a highly developed transport system in C EC. Exposure of endothelium to proinflammatory cytokines (IFN-g, TNF-a and IL-1b) interrupts the BBB by disorganizing cell-cell junctions, decreases the brain solute barrier, enhances leukocyte endothelial adhesion and migration as well as increases expression of class II MHC and promotes shedding of endothelial ‘microparticles’ (EMP). In this review we examine interactions between cytokines/chemokines, activated leukocytes, adhesion molecules and activated C EC in the pathogenesis of BBB failure in MS.

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Zhang, Ling, David Looney, Dennis Taub, Sulie L. Chang, Dennis Way, Marlys H. Witte, Michael C. Graves, and Milan Fiala. "Cocaine opens the blood-brain barrier to HIV-1 invasion." Journal of Neurovirology 4, no. 6 (January 1998): 619–26. http://dx.doi.org/10.3109/13550289809114228.

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Zhu, Longkun, Ravi Maruvada, Adam Sapirstein, Kafait U. Malik, Marc Peters-Golden, and Kwang Sik Kim. "Arachidonic Acid Metabolism Regulates Escherichia coli Penetration of the Blood-Brain Barrier." Infection and Immunity 78, no. 10 (August 9, 2010): 4302–10. http://dx.doi.org/10.1128/iai.00624-10.

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ABSTRACT Escherichia coli K1 meningitis occurs following penetration of the blood-brain barrier, but the underlying mechanisms involved in E. coli penetration of the blood-brain barrier remain incompletely understood. We have previously shown that host cytosolic phospholipase A2α (cPLA2α) contributes to E. coli invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier, but the underlying mechanisms remain unclear. cPLA2α selectively liberates arachidonic acid from membrane phospholipids. Here, we provide the first direct evidence that host 5-lipoxygenase and lipoxygenase products of arachidonic acid, cysteinyl leukotrienes (LTs), contribute to E. coli K1 invasion of HBMEC and penetration into the brain, and their contributions involve protein kinase C alpha (PKCα). These findings demonstrate that arachidonic acid metabolism regulates E. coli penetration of the blood-brain barrier, and studies are needed to further elucidate the mechanisms involved with metabolic products of arachidonic acid for their contribution to E. coli invasion of the blood-brain barrier.

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Pacioni, Simone, Quintino Giorgio D’Alessandris, Mariachiara Buccarelli, Alessandra Boe, Maurizio Martini, Luigi Maria Larocca, Giulia Bolasco, Lucia Ricci-Vitiani, Maria Laura Falchetti, and Roberto Pallini. "Brain Invasion along Perivascular Spaces by Glioma Cells: Relationship with Blood–Brain Barrier." Cancers 12, no. 1 (December 19, 2019): 18. http://dx.doi.org/10.3390/cancers12010018.

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The question whether perivascular glioma cells invading the brain far from the tumor bulk may disrupt the blood–brain barrier (BBB) represents a crucial issue because under this condition tumor cells would be no more protected from the reach of chemotherapeutic drugs. A recent in vivo study that used human xenolines, demonstrated that single glioma cells migrating away from the tumor bulk are sufficient to breach the BBB. Here, we used brain xenografts of patient-derived glioma stem-like cells (GSCs) to show by immunostaining that in spite of massive perivascular invasion, BBB integrity was preserved in the majority of vessels located outside the tumor bulk. Interestingly, the tumor cells that invaded the brain for the longest distances traveled along vessels with retained BBB integrity. In surgical specimens of malignant glioma, the area of brain invasion showed several vessels with preserved BBB that were surrounded by tumor cells. On transmission electron microscopy, the cell inter-junctions and basal lamina of the brain endothelium were preserved even in conditions in which the tumor cells lay adjacently to blood vessels. In conclusion, BBB integrity associates with extensive perivascular invasion of glioma cells.

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Kuhlmann, Christoph R. W., Christoph M. Zehendner, Marlis Gerigk, Dorothea Closhen, Bianca Bender, Peter Friedl, and Heiko J. Luhmann. "MK801 blocks hypoxic blood–brain-barrier disruption and leukocyte adhesion." Neuroscience Letters 449, no. 3 (January 2009): 168–72. http://dx.doi.org/10.1016/j.neulet.2008.10.096.

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Tkáčová, Z., E. Káňová, I. Jiménez-Munguía, Ľ. Čomor, I. Širochmanová, K. Bhide, and M. Bhide. "Crossing the Blood-Brain Barrier by Neuroinvasive Pathogens." Folia Veterinaria 62, no. 1 (March 1, 2018): 44–51. http://dx.doi.org/10.2478/fv-2018-0007.

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Abstract The penetration of the blood-brain barrier (BBB) and invasion of the central nervous system (CNS) are important steps for all neuroinvasive pathogens. All of the ways of pathogens passing through the BBB are still unclear. Among known pathways, pathogen traversal can occur paracellularly, transcellularly or using a “Trojan horse” mechanism. The first step of translocation across the BBB is the interactions of the pathogen’s ligands with the receptors of the host brain cells. Lyme disease, the most common vector-borne disease in the temperate zones of Europe and North America, are caused by Borreliella species (former Borrelia burgdorferi sensu lato) that affects the peripheral and the CNS. In this review, we have presented various pathogen interactions with endothelial cells, which allow the disruption of the BBB so that the pathogens can pass across the BBB.

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Szmydynger-Chodobska, Joanna, Nathalie Strazielle, Jessica R. Gandy, Timothy H. Keefe, Brian J. Zink, Jean-François Ghersi-Egea, and Adam Chodobski. "Posttraumatic Invasion of Monocytes across the Blood—Cerebrospinal Fluid Barrier." Journal of Cerebral Blood Flow & Metabolism 32, no. 1 (August 10, 2011): 93–104. http://dx.doi.org/10.1038/jcbfm.2011.111.

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The invasion of inflammatory cells occurring after ischemic or traumatic brain injury (TBI) has a detrimental effect on neuronal survival and functional recovery after injury. We have recently demonstrated that not only the blood-brain barrier, but also the blood-cerebrospinal fluid (CSF) barrier (BCSFB), has a role in posttraumatic recruitment of neutrophils. Here, we show that TBI results in a rapid increase in synthesis and release into the CSF of a major chemoattractant for monocytes, CCL2, by the choroid plexus epithelium, a site of the BCSFB. Using an in vitro model of the BCSFB, we also show that CCL2 is released across the apical and basolateral membranes of the choroidal epithelium, a pattern of chemokine secretion that promotes leukocyte migration across epithelial barriers. Immunohistochemical and electron microscopic analyses of choroidal tissue provide evidence for the movement of monocytes, sometimes in tandem with neutrophils, along the paracellular pathways between adjacent epithelial cells. These data further support the pathophysiological role of BCSFB in promoting the recruitment of inflammatory cells to the injured brain.

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Petrali, John P., Donald M. Maxwell, and Kenneth R. Mills. "Effects of soman on rat blood-brain barrier." Proceedings, annual meeting, Electron Microscopy Society of America 44 (August 1986): 350–51. http://dx.doi.org/10.1017/s0424820100143377.

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Soman, an organophosphorous irreversible inhibitor of acetylcholinesterase was studied for its effect on the rat blood- brain barrier (BBB) during the first 24 hours of intoxication. Young adult male Sprague-Dawley rats injected with Evans blue dye (1. V. 2ml/kg of a 2% solution) and surviving a subsequent single convulsive dose of Soman (0.9 LD50) presented focal and diffuse penetration of dye in areas of brain normally considered protected by the BBB. Invasion was widest during the the first hour, when signs of excitation, respiratory distress, and convulsions peaked and was absent at 24 hours. During this time period, acetylcholinesterase inhibition, as measured by enzyme assay, persisted in brain and blood at 10 percent and 6 percent of control values respectively. Brains of nonconvulsing animals and animals pretreated with sodium pentobarbital (45mg/kg) or with diazepam (10 mg/kg) were free of extravasated dye.

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Yeung, Dennis, Janet L. Manias, Duncan J. Stewart, and Sukriti Nag. "Decreased junctional adhesion molecule-A expression during blood–brain barrier breakdown." Acta Neuropathologica 115, no. 6 (March 21, 2008): 635–42. http://dx.doi.org/10.1007/s00401-008-0364-4.

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Yau, Belinda, Nicholas Hunt, Andrew Mitchell, and Lay Too. "Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis." International Journal of Molecular Sciences 19, no. 11 (November 11, 2018): 3555. http://dx.doi.org/10.3390/ijms19113555.

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Streptococcus pneumoniae is a major meningitis-causing pathogen globally, bringing about significant morbidity and mortality, as well as long-term neurological sequelae in almost half of the survivors. Subsequent to nasopharyngeal colonisation and systemic invasion, translocation across the blood‒brain barrier (BBB) by S. pneumoniae is a crucial early step in the pathogenesis of meningitis. The BBB, which normally protects the central nervous system (CNS) from deleterious molecules within the circulation, becomes dysfunctional in S. pneumoniae invasion due to the effects of pneumococcal toxins and a heightened host inflammatory environment of cytokines, chemokines and reactive oxygen species intracranially. The bacteria‒host interplay within the CNS likely determines not only the degree of BBB pathological changes, but also host survival and the extent of neurological damage. This review explores the relationship between S. pneumoniae bacteria and the host inflammatory response, with an emphasis on the BBB and its roles in CNS protection, as well as both the acute and long-term pathogenesis of meningitis.

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Engelhardt, Britta. "β1-Integrin/Matrix Interactions Support Blood–Brain Barrier Integrity." Journal of Cerebral Blood Flow & Metabolism 31, no. 10 (July 20, 2011): 1969–71. http://dx.doi.org/10.1038/jcbfm.2011.98.

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Brain microvascular endothelium forms an active permeability barrier, the blood–brain barrier (BBB). In neurologic disorders, barrier properties of the BBB are often lost indicating their dependance on molecular cues of the brain microenvironment. In this issue, Osada et al demonstrate that the endothelial extracellular matrix (ECM) provides one of these cues. Their study shows that β1-integrin-mediated adhesion of brain endothelial cells to the surrounding ECM is critical for stabilizing claudin-5 in BBB tight junctions (TJs) and BBB integrity. These observations point to a novel intracellular signaling pathway from β1-integrin/ECM endothelial adhesions to BBB TJs contributing to BBB integrity.

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Starzyk, Ruth M., Carsten Rosenow, James Frye, Michaela Leismann, Eva Rodzinski, Scott Putney, and Elaine I. Tuomanen. "Cerebral Cell Adhesion Molecule: A Novel Leukocyte Adhesion Determinant on Blood‐Brain Barrier Capillary Endothelium." Journal of Infectious Diseases 181, no. 1 (January 2000): 181–87. http://dx.doi.org/10.1086/315163.

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Lécuyer, Marc-André, Olivia Saint-Laurent, Lyne Bourbonnière, Sandra Larouche, Catherine Larochelle, Laure Michel, Marc Charabati, et al. "Dual role of ALCAM in neuroinflammation and blood–brain barrier homeostasis." Proceedings of the National Academy of Sciences 114, no. 4 (January 9, 2017): E524—E533. http://dx.doi.org/10.1073/pnas.1614336114.

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Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule found on blood–brain barrier endothelial cells (BBB-ECs) that was previously shown to be involved in leukocyte transmigration across the endothelium. In the present study, we found that ALCAM knockout (KO) mice developed a more severe myelin oligodendrocyte glycoprotein (MOG)35–55–induced experimental autoimmune encephalomyelitis (EAE). The exacerbated disease was associated with a significant increase in the number of CNS-infiltrating proinflammatory leukocytes compared with WT controls. Passive EAE transfer experiments suggested that the pathophysiology observed in active EAE was linked to the absence of ALCAM on BBB-ECs. In addition, phenotypic characterization of unimmunized ALCAM KO mice revealed a reduced expression of BBB junctional proteins. Further in vivo, in vitro, and molecular analysis confirmed that ALCAM is associated with tight junction molecule assembly at the BBB, explaining the increased permeability of CNS blood vessels in ALCAM KO animals. Collectively, our data point to a biologically important function of ALCAM in maintaining BBB integrity.

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Maruvada, Ravi, Longkun Zhu, Donna Pearce, Adam Sapirstein, and Kwang Sik Kim. "Host Cytosolic Phospholipase A2α Contributes to Group B Streptococcus Penetration of the Blood-Brain Barrier." Infection and Immunity 79, no. 10 (August 8, 2011): 4088–93. http://dx.doi.org/10.1128/iai.05506-11.

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ABSTRACTGroup BStreptococcus(GBS) is the most common bacterium causing neonatal meningitis, and neonatal GBS meningitis continues to be an important cause of mortality and morbidity. Here we provide the first direct evidence that host cytosolic phospholipase A2α (cPLA2α) contributes to type III GBS invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier and penetration into the brain, the key step required for the development of GBS meningitis. This was shown by our demonstration that pharmacological inhibition and gene deletion of cPLA2α significantly decreased GBS invasion of the HBMEC monolayer and penetration into the brain. cPLA2α releases arachidonic acid from membrane phospholipids, and we showed that the contribution of cPLA2α to GBS invasion of HBMEC involved lipoxygenated metabolites of arachidonic acid, cysteinyl leukotrienes (LTs). In addition, type III GBS invasion of the HBMEC monolayer involves protein kinase Cα (PKCα), as shown by time-dependent PKCα activation in response to GBS as well as decreased GBS invasion in HBMEC expressing dominant-negative PKCα. PKCα activation in response to GBS, however, was abolished by inhibition of cPLA2α and cysteinyl LTs, suggesting that cPLA2α and cysteinyl LTs contribute to type III GBS invasion of the HBMEC monolayer via PKCα. These findings demonstrate that specific host factors involving cPLA2α and cysteinyl LTs contribute to type III GBS penetration of the blood-brain barrier and their contribution involves PKCα.

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Rössler, K., C. Neuchrist, K. Kitz, O. Scheiner, D. Kraft, and H. Lassmann. "Expression of leucocyte adhesion molecules at the human blood-brain barrier (BBB)." Journal of Neuroscience Research 31, no. 2 (February 1992): 365–74. http://dx.doi.org/10.1002/jnr.490310219.

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Lassmann, H., K. Rössler, F. Zimprich, and K. Vass. "Expression of Adhesion Molecules and Histocompatibility Antigens at the Blood-Brain Barrier." Brain Pathology 1, no. 2 (January 1991): 115–23. http://dx.doi.org/10.1111/j.1750-3639.1991.tb00648.x.

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Crockett, Alexis M., Sean K. Ryan, Adriana Hernandez Vásquez, Caroline Canning, Nickole Kanyuch, Hania Kebir, Guadalupe Ceja, et al. "Disruption of the blood–brain barrier in 22q11.2 deletion syndrome." Brain 144, no. 5 (April 20, 2021): 1351–60. http://dx.doi.org/10.1093/brain/awab055.

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Abstract Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia. As the blood−brain barrier is the immunological interface between the brain and the periphery, we investigated whether this vascular phenotype is intrinsically compromised in the most common genetic risk factor for schizophrenia, the 22q11.2 deletion syndrome (22qDS). Blood−brain barrier like endothelium differentiated from human 22qDS+schizophrenia-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 was upregulated in 22qDS+schizophrenia-induced blood–brain barrier and in 22qDS mice, indicating compromise of the blood–brain barrier immune privilege. This immune imbalance resulted in increased migration/activation of leucocytes crossing the 22qDS+schizophrenia blood−brain barrier. We also found heightened astrocyte activation in murine 22qDS, suggesting that the blood−brain barrier promotes astrocyte-mediated neuroinflammation. Finally, we substantiated these findings in post-mortem 22qDS brain tissue. Overall, the barrier-promoting and immune privilege properties of the 22qDS blood–brain barrier are compromised, and this might increase the risk for neuropsychiatric disease.

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Rom, Slava, Viviana Zuluaga-Ramirez, Holly Dykstra, Nancy L. Reichenbach, Servio H. Ramirez, and Yuri Persidsky. "Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions." Journal of Cerebral Blood Flow & Metabolism 35, no. 1 (September 24, 2014): 28–36. http://dx.doi.org/10.1038/jcbfm.2014.167.

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Blood—brain barrier (BBB) dysfunction seen in neuroinflammation contributes to mortality and morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. Identification of molecular targets maintaining barrier function is of clinical relevance. We used a novel in vivo model of localized aseptic meningitis where tumor necrosis factor alpha (TNFα) was introduced intracerebrally and surveyed cerebral vascular changes and leukocyte—endothelium interactions by intravital videomicroscopy. Poly(ADP-ribose) polymerase-1 (PARP) inhibition significantly reduced leukocyte adhesion to and migration across brain endothelium in cortical microvessels. PARP inactivation diminished BBB permeability in an in vivo model of systemic inflammation. PARP suppression in primary human brain microvascular endothelial cells (BMVEC), an in vitro model of BBB, enhanced barrier integrity and augmented expression of tight junction proteins. PARP inhibition in BMVEC diminished human monocyte adhesion to TNFα-activated BMVEC (up to 65%) and migration (80–100%) across BBB models. PARP suppression decreased expression of adhesion molecules and decreased activity of GTPases (controlling BBB integrity and monocyte migration across the BBB). PARP inhibitors down-regulated expression of inflammatory genes and dampened secretion of pro-inflammatory factors increased by TNFα in BMVEC. These results point to PARP suppression as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation.

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Gendelman, Howard E., Jay Rappaport, and William Hickey. "The blood-brain barrier: a defensive shield or a perpetrator of microbial invasion?" Journal of Neurovirology 5, no. 6 (January 1999): 533–37. http://dx.doi.org/10.3109/13550289909021283.

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Fang, Wei, Zhen-Zong Fa, Qun Xie, Gui-Zhen Wang, Jiu Yi, Chao Zhang, Guang-Xun Meng, Ju-Lin Gu, and Wan-Qing Liao. "Complex Roles of Annexin A2 in Host Blood-Brain Barrier Invasion byCryptococcus neoformans." CNS Neuroscience & Therapeutics 23, no. 4 (January 28, 2017): 291–300. http://dx.doi.org/10.1111/cns.12673.

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Stie, Jamal, and Deborah Fox. "Induction of Brain Microvascular Endothelial Cell Urokinase Expression by Cryptococcus neoformans Facilitates Blood-Brain Barrier Invasion." PLoS ONE 7, no. 11 (November 8, 2012): e49402. http://dx.doi.org/10.1371/journal.pone.0049402.

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Woo, Yeon Hwa, and Luis R. Martinez. "Cryptococcus neoformans–astrocyte interactions: effect on fungal blood brain barrier disruption, brain invasion, and meningitis progression." Critical Reviews in Microbiology 47, no. 2 (January 21, 2021): 206–23. http://dx.doi.org/10.1080/1040841x.2020.1869178.

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Wang, Dong, Shi-Ping Li, Jin-Sheng Fu, Sheng Zhang, Lin Bai, and Li Guo. "Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice." Journal of Neurophysiology 116, no. 5 (November 1, 2016): 2173–79. http://dx.doi.org/10.1152/jn.00510.2016.

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The mouse autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), is primarily characterized as dysfunction of the blood-brain barrier (BBB). Resveratrol exhibits anti-inflammatory, antioxidative, and neuroprotective activities. We investigated the beneficial effects of resveratrol in protecting the integrity of the BBB in EAE mice and observed improved clinical outcome in the EAE mice after resveratrol treatment. Evans blue (EB) extravasation was used to detect the disruption of BBB. Western blot were used to detected the tight junction proteins and adhesion molecules zonula occludens-1 (ZO-1), occludin, ICAM-1, and VCAM-1. Inflammatory factors inducible nitric oxide synthase (iNOS), IL-1β, and arginase 1 were evaluated by quantitative RT-PCR (qPCR) and IL-10 by ELISA. NADPH oxidase (NOX) levels were evaluated by qPCR, and its activity was analyzed by lucigenin-derived chemiluminescence. Resveratrol at doses of 25 and 50 mg/kg produced a dose-dependent decrease in EAE paralysis and EB leakage, ameliorated EAE-induced loss of tight junction proteins ZO-1, occludin, and claudin-5, as well as repressed the EAE-induced increase in adhesion proteins ICAM-1 and VCAM-1. In addition, resveratrol suppressed the EAE-induced overexpression of proinflammatory transcripts iNOS and IL-1β and upregulated the expression of anti-inflammatory transcripts arginase 1 and IL-10 cytokine in the brain. Furthermore, resveratrol downregulated the overexpressed NOX2 and NOX4 in the brain and suppressed NADPH activity. Resveratrol ameliorates the clinical severity of MS through maintaining the BBB integrity in EAE mice.

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Duan, Sijia, Xuliang Luo, Huihui Zeng, Xiang Zhan, and Chunlei Yuan. "SNORA71B promotes breast cancer cells across blood–brain barrier by inducing epithelial-mesenchymal transition." Breast Cancer 27, no. 6 (May 23, 2020): 1072–81. http://dx.doi.org/10.1007/s12282-020-01111-1.

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Abstract Background Brain metastasis (BM) is a dreadful complication that significantly impacts the quality of life in breast cancer patients. A key process during brain metastasis is the migration of cancer cells across blood–brain barrier (BBB). However, the role of snoRNAs regulating BBB in BM is still unknown. Methods Here SNORic and GEO databases were used to identify differentially expressed snoRNAs between brain metastatic and non-metastatic breast cancer (BC) tissues. The effects of SNORA71B on the capacities of proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and BBB invasion of BC cells were evaluated by CCK8, transwell, western blot, and BBB model, respectively. Results SNORA71B was highly expressed in high BM BC tissues and cells compared to low BM BC controls. Survival analysis revealed high expression of SNORA71B was significantly associated with poor PPS and OS in breast cancer patients. ROC curve showed that SNORA71B might act as biomarker for breast cancer. Moreover, SNORA71B significantly promoted proliferation, migration, and invasion of BC cells with different BM abilities. Importantly, SNORA71B promoted the EMT process of low BM BC cells. SNORA71B knockdown inhibited the high BM BC cells across BBB, while EMT activator dramatically abrogated this inhibited effect. Conclusions In conclusion, SNORA71B promotes BC cells across the BBB partly via inducing EMT.

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Journal articles on the topic 'Adhesion and Invasion of the blood brain barrier'

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