The blood-brain barrier (BBB) is formed by brain capillary endothelial cells, astrocytes, pericytes, microglia, and neurons. BBB disruption under pathological conditions such as neurodegenerative disease and inflammation is observed in parallel with microglial activation. To test whether activation of microglia is linked to BBB dysfunction, we evaluated the effect of lipopolysaccharide (LPS) on BBB functions in an in vitro co-culture system with rat brain microvascular endothelial cells (RBEC) and microglia. When LPS was added for 6 h to the abluminal side of RBEC/microglia co-culture at a concentration showing no effects on the RBEC monolayer, transendothelial electrical resistance was decreased and permeability to sodium-fluorescein was increased in RBEC. Immunofluorescence staining for tight junction proteins demonstrated that zonula occludens-1-, claudin-5-, and occludin-like immunoreactivities at the intercellular borders of RBEC were fragmented in the presence of LPS-activated microglia. These functional changes induced by LPS-activated microglia were blocked by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, diphenyleneiodonium chloride. The present findings suggest that LPS activates microglia to induce dysfunction of the BBB by producing reactive oxygen species through NADPH oxidase.
Abstract. The present study was designed to elucidate the involvement of tumor necrosis factor-α (TNF-α ) release from activated microglia in the induction of blood-brain barrier (BBB) dysfunction in an in vitro co-culture system with mouse brain capillary endothelial cells (MBEC4) and microglia. Lipopolysaccharide (LPS)-activated microglia increased the permeability of MBEC4 cells to sodium-fluorescein, and this hyper-permeability was blocked by a neutralizing antibody against TNF-α . LPS stimulated microglia to facilitate TNF-α release. These findings suggested that TNF-α released from activated microglia is attributable to BBB dysfunction.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Benzodiazepines, antidepressants, antipsychotic agents, anti-arrhythmic agents, opioid analgesics and antihypertensive agents including a-receptor antagonists and b-receptor antagonists, but not angiotensin II receptor antagonists, have been implicated as risk factors for falls among community dwelling elderly people, and those in aged care hospitals and nursing homes.
WHAT THIS STUDY ADDS• Using a case-crossover design, the study's findings provide the first evidence suggesting that newly initiating treatment using an angiotensin II receptor antagonist, candesartan, or etizolam, biperiden and zopiclone may be potential risk factors for falls in acute hospitals.
AIMSThe present study aimed to evaluate the associations between medication use and falls and to identify high risk medications that acted as a trigger for the onset of falls in an acute care hospital setting.
METHODSWe applied a case-crossover design wherein cases served as their own controls and comparisons were made within each participant. The 3-day period (days 0 to -2) and the 3-day periods (days -6 to -8, days -9 to -11 and days -12 to -14) before the fall event were defined as the case period and the control periods, respectively. Exposures to medications were compared between the case and control periods. Odds ratios (OR) and 95% confidence intervals (CI) for the onset of falls with respect to medication use were computed using conditional logistic regression analyses.
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