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

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

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number24
JournalFluids and Barriers of the CNS
Volume8
Issue number1
DOIs
Publication statusPublished - 2011 Oct 21

Keywords

  • Blood-brain barrier
  • Inflammation
  • Lipopolysaccharide
  • MRP4
  • Multidrug resistance-associated protein
  • Oat3
  • Oatp1a4
  • PGE2
  • Prostaglandin
  • Transporter

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

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