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Role of the blood–cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E 2 produced in the brain
Author(s) -
Tachikawa Masanori,
Ozeki Go,
Higuchi Takanori,
Akanuma Shinichi,
Tsuji Kazuhiro,
Hosoya Kenichi
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12018
Subject(s) - prostaglandin e , cerebrospinal fluid , choroid plexus , chemistry , prostaglandin , blood–brain barrier , endocrinology , medicine , biochemistry , biology , central nervous system
An increasing level of prostaglandin ( PG ) E 2 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 PGE 2 in the cerebrospinal fluid ( CSF ), the regulatory system remains incompletely understood. The purpose of this study was to investigate the cellular system of PGE 2 production via microsomal PGE synthetase‐1 ( mPGES ‐1), the inducible PGE 2 ‐generating enzyme, and PGE 2 elimination from the CS F 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 PGE 2 in the CSF . The in vivo PGE 2 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 PGE 2 and β‐lactam antibiotics, such as benzylpenicillin, cefazolin, and ceftriaxone, which are substrates and/or inhibitors of organic anion transporter 3 ( OAT 3). The characteristics of PGE 2 uptake by the isolated choroid plexus were at least partially consistent with those of OAT 3. OAT 3 was able to mediate PGE 2 transport with a Michaelis–Menten constant of 4.24 μM. These findings indicate that a system regulating the PGE 2 level in the CSF involves OAT 3‐mediated PGE 2 uptake by choroid plexus epithelial cells, acting as a cerebral clearance pathway via the BCSFB of locally produced PGE 2 .