Rapid modulation of Pglycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-ĮDQG lipopolysaccharide. Molecular pharmacology 2006

At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain paren-chyma, impeding pharmacotherapy of a number of central ner-vous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ETB receptor, NO syn-thase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain’s innate immune response and functional regulation of P-glycoprotein. We show that exposing brain cap-illaries to the inflammatory cytokine tumor necrosis factor- (TNF-), activated a TNF-R1 receptor, released ET-1, activated ETB receptor signaling, and essentially abolished P-glycopro-tein-mediated transport. Bacterial lipopolysaccharide, a poten