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: [(3)H]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 [(3)H]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.