Role of the blood-cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E₂ produced in the brain

An increasing level of prostaglandin (PG) E₂ is involved in the progression of neuroinflammation induced by ischemia and bacterial infection. Although an imbalance in the rates of production and clearance of PGE ₂ under these pathological conditions appears to affect the concentration of PGE₂ in the cerebrospinal fluid (CSF), the regulatory system remains incompletely understood. The purpose of this study was to investigate the cellular system of PGE₂ production via microsomal PGE synthetase-1 (mPGES-1), the inducible PGE₂-generating enzyme, and PGE₂ elimination from the CSF via the blood-CSF barrier (BCSFB). Immunohistochemical analysis revealed that mPGES-1 was expressed in the soma and perivascular sheets of astrocytes, pia mater, and brain blood vessel endothelial cells, suggesting that these cells are local production sites of PGE₂ in the CSF. The in vivo PGE₂ elimination clearance from the CSF was eightfold greater than that of d-mannitol, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGE₂ and β-lactam antibiotics, such as benzylpenicillin, cefazolin, and ceftriaxone, which are substrates and/or inhibitors of organic anion transporter 3 (OAT3). The characteristics of PGE₂ uptake by the isolated choroid plexus were at least partially consistent with those of OAT3. OAT3 was able to mediate PGE₂ transport with a Michaelis-Menten constant of 4.24 μM. These findings indicate that a system regulating the PGE₂ level in the CSF involves OAT3-mediated PGE₂ uptake by choroid plexus epithelial cells, acting as a cerebral clearance pathway via the BCSFB of locally produced PGE ₂.