title: A clearance system for prostaglandin D2, a sleep-promoting factor, in cerebrospinal fluid: role of the blood-cerebrospinal barrier transporters.
abstract: Although the level of prostaglandin (PG) D(2) in cerebrospinal fluid (CSF) affects the action of D-type prostanoid receptors that promote physiological sleep, the regulatory system of PGD(2) clearance from the CSF is not fully understood. The purpose of this study was to investigate PGD(2) elimination from the CSF via the blood-CSF barrier (BCSFB). The in vivo PGD(2) elimination clearance from the CSF was 16-fold greater than that of inulin, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGD(2). The characteristics of PGD(2) uptake by isolated choroid plexus were, at least partially, consistent with those of PG transporter (PGT) and organic anion transporter 3 (OAT3). Studies using an oocyte expression system showed that PGT and OAT3 were able to mediate PGD(2) transport with a Michaelis-Menten constant of 1.07 and 7.32 μM, respectively. Reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that PGT was localized on the brush-border membrane of the choroid plexus epithelial cells. These findings indicate that the system regulating the PGD(2) level in the CSF involves PGT- and OAT3-mediated PGD(2) uptake by the choroid plexus epithelial cells, acting as a pathway for PGD(2) clearance from the CSF via the BCSFB.
authors.affiliation: Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuji
authors.forename: Reiji
authors.initials: R
authors.lastname: Yokoyama
authors.forename: Takanori
authors.initials: T
authors.lastname: Higuchi
authors.forename: Go
authors.initials: G
authors.lastname: Ozeki
authors.forename: Ayane
authors.initials: A
authors.lastname: Yashiki
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Akanuma
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hayashi
authors.forename: Akio
authors.initials: A
authors.lastname: Nishiura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hosoya
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002831:Choroid Plexus / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012890:Sleep / Q000502:physiology*; D014018:Tissue Distribution; D014982:Xenopus laevis
chemical_list: D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503527:Slco2a1 protein, mouse; C114338:organic anion transport protein 3; D015230:Prostaglandin D2