A clearance system for prostaglandin D₂, a sleep-promoting factor, in cerebrospinal fluid: Role of the blood-cerebrospinal barrier transporters

Although the level of prostaglandin (PG) D₂ in cerebrospinal fluid (CSF) affects the action of D-type prostanoid receptors that promote physiological sleep, the regulatory system of PGD₂ clearance from the CSF is not fully understood. The purpose of this study was to investigate PGD₂ elimination from the CSF via the blood-CSF barrier (BCSFB). The in vivo PGD₂ 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 PGD₂. The characteristics of PGD₂ 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 PGD₂ 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 PGD₂ level in the CSF involves PGT- and OAT3-mediated PGD₂ uptake by the choroid plexus epithelial cells, acting as a pathway for PGD₂ clearance from the CSF via the BCSFB.