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

Abstract

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...

The impact of inflammation on respiratory plasticity

“…E. coli , salmonella , and other gram negative bacteria contain LPS, but the structure of the lipid component of LPS can differ between organisms, with some LPS molecules having more potent effects, likely due to changes in how they interact with TLRs (Jin et al, 2013; Li et al, 2013; Rietschel et al, 1994). High doses (>10 mg/kg in rats, >7 mg/kg in mice) of LPS cause sepsis and high mortality and even more moderate doses (5-6 mg/kg) of LPS can cause progressive neurodegeneration (Cardoso et al, 2015; Qin et al, 2007), long-term behavioral changes, and decreased neural markers of hippocampal plasticity (Anderson et al, 2015).…”

Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit

“…Recent animal studies have illustrated that LPS exposure in pregnant mice elevates fetal IL-6 and perturbs fetal brain development [7, 13]. Other data collected in rodents suggest that the BBB is relatively impermeable to LPS [14]. While the rodent work is compelling, it can be difficult to reconcile with human postmortem studies [15, 16] and observations made in cell culture, which seem to indicate a much more pronounced effect of LPS on the BBB [17].…”

Polymyxins–Curcumin Combination Antimicrobial Therapy: Safety Implications and Efficacy for Infection Treatment

“…The blood–brain barrier (BBB) is the “first barrier” that mediates the uptake of the drug into neuronal cells in the brain tissues, and it only allows small molecules that both have the low molecular mass (<450 Da) and high lipid solubility to pass [ 123 ]. The tight junctions of the interendothelial domains limit the passage of large hydrophilic molecules cross the BBB and this is considered as the main reason underlying the low BBB penetration of polymyxins (molecular mass of colistin and polymyxin B are ~1155 Da and ~1, 203, respectively) [ 124 ]. This may also explain the higher incidence in peripheral nervous system (PNS)- than CNS- mediated polymyxin neurotoxicity in clinic [ 117 , 119 , 125 ].…”

“…This may also explain the higher incidence in peripheral nervous system (PNS)- than CNS- mediated polymyxin neurotoxicity in clinic [ 117 , 119 , 125 ]. It is negligible in the brain uptake of colistin when healthy mice were received a single intravenous dose (5 mg/kg) or subcutaneous dose (40 mg/kg) [ 124 , 126 , 127 , 128 ]. However, Wang et al, showed that the continuous administration of intravenous colistin sulfate at 15 mg/kg/day for 7 days to mice significantly increased the colistin concentration in brain tissues without BBB damage [ 129 ].…”