Attenuation of prostaglandin E 2elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole

Abstract

Background: Peripheral administration of lipopolysaccharide (LPS) induces inflammation and increases cerebral prostaglandin E 2(PGE 2) concentration. PGE 2is eliminated from brain across the blood-brain barrier (BBB) in mice, and this process is inhibited by intracerebral or intravenous pre-administration of anti-inflammatory drugs and antibiotics such as cefmetazole and cefazolin that inhibit multidrug resistance-associated protein 4 (Mrp4/Abcc4)-mediated PGE 2transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE 2elimination from brain, and whether antibiotics further inhibit PGE 2elimination in LPS-treated mice.Methods: [ 3H]PGE 2elimination across the BBB of intraperitoneally LPS-treated mice was assessed by the brain efflux index (BEI) method. Transporter protein amounts in brain capillaries were quantified by liquid chromatography-tandem mass spectrometry.Results: The apparent elimination rate of [ 3H]PGE 2from brain was lower by 87%, in LPS-treated mice compared with saline-treated mice. The Mrp4 protein amount was unchanged in brain capillaries of LPS-treated mice compared with saline-treated mice, while the protein amounts of organic anion transporter 3 (Oat3/Slc22a8) and organic anion transporting polypeptide 1a4 (Oatp1a4/Slco1a4) were decreased by 26% and 39%, respectively. Either intracerebral or intravenous pre-administration of cefmetazole further inhibited PGE 2elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE 2elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE 2elimination across the BBB in LPS-treated mice.Conclusion: PGE 2elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE 2elimination in LPS-treated mice. © 2011 Akanuma et al; licensee BioMed Central Ltd.