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

Background: Peripheral administration of lipopolysaccharide (LPS) induces inflammation and increases cerebral prostaglandin E ₂ (PGE ₂) concentration. PGE ₂ is 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 ₂ transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE ₂ elimination from brain, and whether antibiotics further inhibit PGE ₂ elimination in LPS-treated mice.Methods: [ ³H]PGE ₂ elimination 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 ₂ from 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 ₂ elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE ₂ elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE ₂ elimination across the BBB in LPS-treated mice.Conclusion: PGE ₂ elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE ₂ elimination in LPS-treated mice.