Abstract
P-glycoprotein (P-gp) is a brain-to-blood efflux system that controls the ability of many drugs and endogenous substances to access the brain. In vitro work has shown that inflammatory states mediated through lipopolysaccharide (LPS) and tumor necrosis factor-alpha first impair and then stimulate P-gp activity. Here, we determined whether LPS can affect P-gp function in vivo. Mice treated with a single intraperitoneal injection of LPS (3 mg/kg) showed an inhibition of P-gp function. As assessed by brain perfusion, inhibition began 18 h after LPS administration and lasted until 36 h after administration. P-gp protein was increased by 44%, consistent with P-gp inhibition occurring through post-translational mechanisms. Unlike other effects of LPS on blood–brain barrier function, neither nitric oxide nor prostaglandin inhibition had an effect. We conclude that induction of proinflammatory states as exemplified by LPS treatment can inhibit P-gp function in vivo at the blood–brain barrier.
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Support: VA merit review; R01 NS051334; R01 NS050547; R01 AG029839.
This work has not been previously presented at a meeting, but was presented in part as a poster at the June 2008 Gordon Conference on blood–brain barrier.
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Salkeni, M.A., Lynch, J.L., Otamis-Price, T. et al. Lipopolysaccharide Impairs Blood–Brain Barrier P-glycoprotein Function in Mice Through Prostaglandin- and Nitric Oxide-Independent Pathways. J Neuroimmune Pharmacol 4, 276–282 (2009). https://doi.org/10.1007/s11481-008-9138-y
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DOI: https://doi.org/10.1007/s11481-008-9138-y