Inflammation-Induced Attenuation of Prostaglandin D 2 Elimination across Rat Blood-Brain Barrier: Involvement of the Downregulation of Organic Anion Transporter 3 and Multidrug Resistance-Associated Protein 4.

Prostaglandin (PG) D ₂ is a lipid mediator, and in the brain, overproduction of PGD ₂ is reportedly involved in the progression and exacerbation of neuroinflammation. The objective of this study was to elucidate PGD ₂ efflux transport, under normal and inflammatory conditions, across the blood-brain barrier (BBB), which is formed by brain capillaries. Elimination of [ ³ H]PGD ₂ across the BBB of normal and lipopolysaccharide (LPS)-induced inflammatory rats was examined by the intracerebral microinjection technique. After intracerebral injection, the percentage of [ ³ H]PGD ₂ remaining in the ipsilateral cerebrum decreased with time, with a half-life of 13 min. This [ ³ H]PGD ₂ elimination across the BBB was significantly inhibited by the co-administration of unlabeled PGD ₂ , which suggests carrier-mediated PGD ₂ efflux transport at the BBB. In isolated rat brain capillaries, mRNA expression of organic anion transporter (Oat) 3, organic anion-transporting polypeptide (Oatp) 1a4, and multidrug resistance-associated protein (Mrp) 4 was observed. In addition, co-administration of substrates/inhibitors for Oat3, Oatp1a4, and/or Mrp4, such as benzylpenicillin and cefmetazole, reduced [ ³ H]PGD ₂ elimination across the BBB. Data suggest that Oat3 and Mrp4, but not Oatp1a4 are involved in PGD ₂ elimination across the BBB, as Oatp1a4-expressing Xenopus (X.) oocytes did not show the significant [ ³ H]PGD ₂ uptake compared with water-injected X. oocytes. In LPS-treated rats, [ ³ H]PGD ₂ elimination across the BBB and mRNA expression levels of Oat3 and Mrp4 were significantly decreased. Our data suggest that Oat3- and Mrp4-mediated PGD ₂ elimination across the BBB is attenuated under inflammatory conditions.