Lipopolysaccharide Impairs Blood–Brain Barrier P-glycoprotein Function in Mice Through Prostaglandin- and Nitric Oxide-Independent Pathways

Salkeni, Mohamad A.; Lynch, Jessica; Otamis-Price, Tulin; Banks, William A.

doi:10.1007/s11481-008-9138-y

Cited by 63 publications

(65 citation statements)

References 21 publications

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“…We did not reassess the effects of S. enterica LPS on the brain uptake of [ 14 C]sucrose or colistin in the current study, as previous results in our laboratory have demonstrated the effects of S. enterica LPS to be quite reproducible (with a coefficient of variation of 12.2% over 24 replicates) and consistent with reports from other laboratories (28,29). The lack of effect of P. aeruginosa LPS is consistent with our previous observations demonstrating that inoculation of P. aeruginosa did not affect the paracellular integrity of the BBB (15), despite the plasma concentrations of IL-6 and TNF-␣ being substantially increased with both P. aeruginosa inoculation and P. aeruginosa LPS administration.…”

Section: Discussionsupporting

confidence: 84%

Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

Jin

Nation

et al. 2013

Antimicrob Agents Chemother

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The aim of this study was to use in vitro and in vivo models to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS from Pseudomonas aeruginosa, the brain-to-plasma ratio of [ 14 C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS from Salmonella enterica, LPS from P. aeruginosa had no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different (P > 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS from P. aeruginosa or S. enterica and claudin-5 expression was measured by Western blotting. S. enterica LPS significantly (P < 0.05) reduced claudin-5 expression at a concentration of 7.5 g/ml. In contrast, P. aeruginosa LPS decreased (P < 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 g/ml). Coadministration of therapeutic concentrations of colistin ameliorated the S. enterica LPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least between P. aeruginosa and S. enterica, and can be ameliorated by colistin.T he blood-brain barrier (BBB) is formed by specialized endothelial cells of cerebral microvessels. Unlike endothelial cells in other organs, the layer of endothelial cells lining the cerebral microvessels constitutes a physical barrier between blood and brain tissue by a complex network of tight junctions (TJs) (1). The TJs consist of transmembrane proteins spanning the intercellular cleft; these proteins include occludin, claudins (particularly claudin-5) (2), and several cytoplasmic proteins, such as zonula occludens (3). Under normal conditions, these TJ proteins seal the paracellular route of the BBB, thus preventing the movement of relatively small hydrophilic molecules from the blood into the brain, ensuring homeostatic regulation of the central nervous system (CNS) (4).Alterations to TJ proteins and increases in BBB permeability are observed during various disease states, including peripheral hyperalgesia, bacterial meningitis, systemic inflammation, and sepsis (5-8). Indeed, we have demonstrated that systemic administration to mice of lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, from Salmonella enterica (as a model of bacterium-induced inflammation) leads to BBB dysfunction (9). One proposed mechanism for the decreased paracellular integrity of the BBB in response to LPS involves elevated plasma c...

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Section: Discussionsupporting

confidence: 84%

Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

Jin

Nation

et al. 2013

Antimicrob Agents Chemother

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“…This is in contrast to findings in astrocyte-enriched cultures with no cocultivation, where TLR4 is expressed rather sparsely and is more difficult to induce. Although LPS normally does not readily pass the intact BBB, LPS itself can impair the integrity of the BBB and thereby affect the flux system between blood and brain (44). Therefore, although our findings in the present study must primarily be conceived as purely in vitro model data, they may have some bearing also for the understanding of in vivo systemic actions following the release of LPS (e.g.…”

Section: Discussionmentioning

confidence: 94%

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Forshammar

Block

Lundborg

et al. 2011

Journal of Biological Chemistry

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Infection, tissue damage, or other conditions can lead to a neuroinflammatory state. Lipopolysaccharide (LPS) exposure can be used experimentally as a model to generate an inflammatory response both in vitro and in vivo. Endotoxin, or LPS, is a potent inflammatory activator (1) in astrocytes and microglia, with stimulation of Toll-like receptor 4 (TLR4) (2). The expression of TLR4 is up-regulated in astrocytes under neuroinflammatory conditions (3). Activation of TLR4 leads to activation of nuclear factor-B, a factor that regulates expression of genes involved in immune responses, including release of the proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) (2).Astrocytes in networks, positioned between the vasculature and synapses, monitor neuronal signaling, including rebuilding of synapses (4, 5). Astrocytes express almost the same repertoire of receptors and ion channels as neurons. They regulate synaptic transmission via a bidirectional communication with neurons, and they release gliotransmitters as well as factors, including cytokines, fatty acid metabolites, and free radicals (6 -8).The Ca 2ϩ signaling in astrocytes over long distances is analogous to, but much slower than, the propagation of action potentials in neurons (9). These astrocytic Ca 2ϩ waves (10, 11) can be evoked by transmitters released from neurons and glial cells, followed by activation of especially G protein-coupled receptors. Cytosolic Ca 2ϩ plays a key role as a second messenger, and the control of Ca 2ϩ signals is therefore critical. This involves coordination of Ca 2ϩ entry across the plasma membrane (PM), 2 Ca 2ϩ release from the endoplasmatic reticulum (ER), refilling of the ER stores, and extrusion across the PM (12). The Na ϩ -Ca 2ϩ exchanger, a Ca 2ϩ transporter that controls the intracellular Ca 2ϩ concentrations, is driven by the Na ϩ electrochemical gradient across the PM. This Na ϩ pump, Na ϩ /K ϩ -ATPase, indirectly modulates Ca 2ϩ signaling (13), and inflammatory stimuli influence Ca 2ϩ homeostasis in the astrocyte networks (5, 14 -16).The cytoskeleton seems to be important in this system for controlling of PM microdomains and the ER complex. The adaptor protein ankyrin B is associated with the Na ϩ pump and also with ER proteins, such as the inositol 1,4,5-trisphosphate (IP 3 ) receptor. The main cytoplasmic matrix of proteins, spectrin and actin, are attached to ankyrin B. An intact cytoskeleton is required for the propagation of astrocytic Ca 2ϩ waves (17)

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“…A number of studies have reported that Abcb1 gene expression can be regulated by various factors such as steroid hormones (Nuessler et al 1997, Nakayama et al 1999, cellular membrane stretch (Sardini et al 1994, Wang et al 2013, and inflammation (Salkeni et al 2009, Poller et al 2010, Gibson et al 2012. P4 is the major regulatory hormone of pregnancy, essential for the maintenance of pregnancy and uterine growth (Thijssen 2005).…”

Section: Discussionmentioning

confidence: 99%

P-glycoprotein expression and localization in the rat uterus throughout gestation and labor

et al. 2016

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Uterine tissues contain the efflux transporter P-glycoprotein (P-gp, encoded by Abcb1a/1b gene), but little is known about how it changes through gestation. Our aim was to investigate the expression profile and cellular localization of P-gp in the pregnant, laboring and post-partum (PP) rat uterus. We propose that during pregnancy the mechanical and hormonal stimuli play a role in regulating myometrial Abcb1a/1b/P-gp. Samples from bilaterally and unilaterally pregnant rats were collected throughout gestation, during labor, and PP (n = 4-6/gestational day). RNA and protein were isolated and subjected to quantitative PCR and immunoblotting; P-gp transcript and protein were localized by in situ hybridization and immunohistochemistry. Expression of Abcb1a/1b gene and membrane P-gp protein in uterine tissue (1) increased throughout gestation, peaked at term (GD19-21) and dropped during labor (GD23L); and (2) was upregulated only in gravid but not in empty horn of unilaterally pregnant rats. (3) The drop of Abcb1a/1b mRNA on GD23 was prevented by artificial maintenance of elevated progesterone (P4) levels in late gestation; (4) injection of the P4 receptor antagonist RU486 on GD19 caused a significant decrease in Abcb1 mRNA levels. (5) In situ hybridization and immunohistochemistry indicated that Abcb1/P-gp is absent from myometrium throughout gestation; (6) was expressed exclusively by uterine microvascular endothelium (at early gestation) and luminal epithelium (at mid and late gestation), but was undetectable during labor. In conclusion, ABC transporter protein P-gp in pregnant uterus is hormonally and mechanically regulated. However, its substrate(s) and precise function in these tissues during pregnancy remains to be determined. Reproduction (2016) 152 195-204

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Lipopolysaccharide Impairs Blood–Brain Barrier P-glycoprotein Function in Mice Through Prostaglandin- and Nitric Oxide-Independent Pathways

Cited by 63 publications

References 21 publications

Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

P-glycoprotein expression and localization in the rat uterus throughout gestation and labor

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