Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood-brain barrier in vitro.
Lipopolysaccharide-induced changes in blood-brain barrier (BBB) permeability were investigated with a pharmacological approach in vitro. Lipopolysaccharide induced a concentration- and time-dependent (non)reversible opening of the BBB, and brain astrocytes make brain capillary endothelial cells (BCEC) resistant to this BBB disruption. De novo protein synthesis was essential for the recovery, because cycloheximide prevented the recovery process. Dexamethasone pretreated BCEC were more resistant to lipopolysaccharide, while no protective response was induced by heat shock nor by inhibition of P-glycoprotein. BBB opening was tempered by free radical inhibitors (i.e., pretreatment with N-acetyl-cysteine or uric acid combined with deferroxamine mesylate). No effects of modulators of prostanoid-, leukotriene-, or platelet-activating factor pathways were observed. Therefore, lipopolysaccharide-induced BBB opening seems to be primarily mediated by excessive free radical production.
Gaillard
Pieter J
PJ
Blood-Brain Barrier Research Group, Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands. Gaillard@LACDR.LeidenUniv.nl
de Boer
A Bert G
AB
Breimer
Douwe D
DD
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000098:blood supply; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D005609:Free Radicals; D008070:Lipopolysaccharides; D011500:Protein Synthesis Inhibitors; D003907:Dexamethasone; D003513:Cycloheximide