Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole

[3H]PGE2 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.The apparent elimination rate of [3H]PGE2 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 PGE2 elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE2 elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE2 elimination across the BBB in LPS-treated mice.PGE2 elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE2 elimination in LPS-treated mice.The blood-brain barrier (BBB), which is formed by the tight junctions of brain capillary endothelial cells, expresses various transporters to regulate exchange of compounds between the brain and the circulating blood. Organic anion transporters such as multidrug resistance-associated protein 4 (Mrp4/Abcc4), organic anion transporter 3 (Oat3/Slc22a8) and organic anion transporting polypeptide 1a4 (Oatp1a4/Slco1a4) are involved in the elimination of endogenous anionic compounds across the BBB [1]. Mrp4 is expressed at the luminal membrane of the BBB [2], while Oat3 is expressed at the abluminal membrane of the BBB [3]. Oatp1a4 is localized in both the abluminal and luminal membranes [4]. Involvem