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

Shin-Ichi Akanuma,Ken-Ichi Hosoya,Masanori Tachikawa,Tetsuya Terasaki,Sumio Ohtsuki,Yasuo Uchida

doi:10.1186/2045-8118-8-24

Shin-Ichi Akanuma, Ken-Ichi Hosoya + Show 4 more

Open Access

https://doi.org/10.1186/2045-8118-8-24

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Abstract

BackgroundPeripheral administration of lipopolysaccharide (LPS) induces inflammation and increases cerebral prostaglandin E2 (PGE2) concentration. PGE2 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 PGE2 transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE2 elimination from brain, and whether antibiotics further inhibit PGE2 elimination in LPS-treated mice.Methods[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.ResultsThe 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.ConclusionPGE2 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.

Highlights

Peripheral administration of lipopolysaccharide (LPS) induces inflammation and increases cerebral prostaglandin E2 (PGE2) concentration
We have reported that the elimination of PGE2 across the blood-brain barrier (BBB) was inhibited by either intracerebral or intravenous administration of antibiotics, such as cefmetazole and cefazolin, and by intracerebral administration of non-steroidal antiinflammatory drug (NSAIDs), such as indomethacin and ketoprofen
Effect of intraperitoneal pre-administration of LPS on PGE2 elimination from mouse brain Figure 1A shows the time-profile of the percentage of [3H] PGE2 remaining in the ipsilateral cerebrum after microinjection into the S2 region of LPS-treated mouse brain

Summary

Introduction

Peripheral administration of lipopolysaccharide (LPS) induces inflammation and increases cerebral prostaglandin E2 (PGE2) concentration. Intracerebral or intravenous pre-administration of cefazolin had little effect on PGE2 elimination in LPS-treated mice, or in LPS-untreated mice given Oat and Oatp1a4 inhibitors These results indicate that peripheral administration of cefmetazole inhibits PGE2 elimination across the BBB 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]. Because PGE2-metabolizing activity was not detected either in rat brain or cerebral microvessels [7], PGE2 elimination across the BBB is considered to be critical for controlling PGE2 function in the brain

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