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

Prostaglandin (PG) D is a lipid mediator, and in the brain, overproduction of PGD is reportedly involved in the progression and exacerbation of neuroinflammation. The objective of this study was to elucidate PGD efflux transport, under normal and inflammatory conditions, across the blood-brain barrier (BBB), which is formed by brain capillaries. Elimination of [H]PGD across the BBB of normal and lipopolysaccharide (LPS)-induced inflammatory rats was examined by the intracerebral microinjection technique. After intracerebral injection, the percentage of [H]PGD remaining in the ipsilateral cerebrum decreased with time, with a half-life of 13 min. This [H]PGD elimination across the BBB was significantly inhibited by the co-administration of unlabeled PGD, which suggests carrier-mediated PGD 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 [H]PGD elimination across the BBB. Data suggest that Oat3 and Mrp4, but not Oatp1a4 are involved in PGD elimination across the BBB, as Oatp1a4-expressing Xenopus (X.) oocytes did not show the significant [H]PGD uptake compared with water-injected X. oocytes. In LPS-treated rats, [H]PGD elimination across the BBB and mRNA expression levels of Oat3 and Mrp4 were significantly decreased. Our data suggest that Oat3- and Mrp4-mediated PGD elimination across the BBB is attenuated under inflammatory conditions.